@article {pmid39628626,
year = {2024},
author = {Ma, YN and Xia, Y and Karako, K and Song, P and Hu, X},
title = {Extrachromosomal DNA: Molecular perspectives in aging and neurodegenerative diseases.},
journal = {Intractable & rare diseases research},
volume = {13},
number = {4},
pages = {251-254},
pmid = {39628626},
issn = {2186-3644},
abstract = {Extrachromosomal DNA (ecDNA) refers to a class of circular, non-chromosomal DNA that has recently gained widespread attention due to its potential role in aging and neurodegenerative diseases. The generation of ecDNA is closely associated with processes such as double-strand breaks, micronuclei formation, and the breakage-fusion-bridge (BFB) cycle, all of which are integral to regulation of gene expression, genetic stability, and clonal evolution. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, the aberrant formation of ecDNA is closely linked to defects in DNA repair, alterations in synaptic plasticity, and neuronal dysfunction. The distinct distribution and functional roles of ecDNA in these conditions make it a potential diagnostic biomarker and therapeutic target. This review provides an overview of the mechanisms underlying ecDNA formation and its functions in the nervous system. Additionally, it explores the clinical potential of ecDNA in disease diagnosis, targeted therapy, and personalized medicine, offering new insights for future research and treatment strategies.},
}

@article {pmid39628325,
year = {2024},
author = {Elawad, MA and Ayaz, M and Mosa, OF and Usman, A and Hamdoon, AAE and Almawash, S and Salim, LHM and Ahmed, A and Elkhalifa, MEM},
title = {Polyphenols and Their Biogenic Nano-Formulations Targeting BACE1 as Anti-Amyloid Therapies; Meeting the Challenges of Bioavailability, Safety, and Specificity for the Treatment of Alzheimer's Disease.},
journal = {Molecular nutrition & food research},
volume = {},
number = {},
pages = {e2400525},
doi = {10.1002/mnfr.202400525},
pmid = {39628325},
issn = {1613-4133},
abstract = {Alzheimer's disease (AD), a progressiveneurodegenerative condition is marked by extensive damage in the brain and dementia. Among the pathological hallmarks of AD is beta-amyloid (Aβ). Production of toxic Aβ oligomers production and accumulation in the brain is among the characteristic features of the disease. The abnormal accumulation Aβ is initiated by the catalytic degradation of Amyloid Precursor Proteins (APP) by Beta Amyloid Cleaving Enzyme 1 (BACE1) to generate insoluble amyloid plaques. The abnormal proteins are mitochondrial poison which disrupt the energy production and liberate excessive free radicals causing neuronal damage and mutations. Consequently, targeting Aβ-associated pathways has become a focus in the pursuit of developing effective AD treatments. An obstacle faced by many medications used to treat neurodegenerative diseases (NDs) is the restricted permeability across the blood-brain barrier (BBB). Unfortunately, no anti-amyloid drug is clinically approved till now. Recent advancements in nanotechnology have provided a possible solution for delivering medications to specific targets. By integrating natural products with nano-medicinal approaches, it is possible to develop novel and highly efficient therapeutic strategies for the treatment of AD.},
}

@article {pmid39628105,
year = {2024},
author = {Antony, D and Sheth, P and Swenson, A and Smoller, C and Maguire, K and Grossberg, G},
title = {Recent advances in Alzheimer's disease therapy: clinical trials and literature review of novel enzyme inhibitors targeting amyloid precursor protein.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1080/14656566.2024.2438317},
pmid = {39628105},
issn = {1744-7666},
abstract = {INTRODUCTION: Amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimer's disease (AD), the leading cause of dementia worldwide. The accumulation of beta-amyloid protein is believed to be a crucial step in the development of AD. Therefore, understanding the complex biology of APP and its various cleavage products may be useful for developing effective therapeutic strategies for AD.

AREAS COVERED: This paper focuses on APP and its effects on the pathogenesis of AD to develop avenues for intervention. The amyloidogenic pathway of APP processing involves proteolytic cleavage by two prominent secretases, γ-Secretase and β-secretase. The therapeutic potential of blocking β-amyloid accumulation through inhibiting these two secretases has been theorized. In the late 2000s, multiple pharmaceutical drugs that inhibited γ-Secretase and β-Secretase were synthesized, some of which advanced to human clinical trials. Unfortunately, neither γ-Secretase nor β-secretase inhibitors have been approved by the FDA due to both lack of efficacy and concerns for serious side effects. These clinical trials, why they failed, and the future of targeting secretase enzymes represent the central focus of our paper.

EXPERT OPINION: While targeting of Aβ accumulation through secretase inhibitors was halted due to severe side effects, γ-Secretase modulators (GSMs) have arisen as a potential alternative approach. The first generation of GSM's were derived from NSAIDs and could modulate γ-secretase activity without affecting Notch cleavage. However, to improve potency and brain penetration, second-generation GSMs were developed to reduce levels of the amylogenic form of Aβ, Aβ42, without affecting the NOTCH signaling pathway. Several of these drugs have progressed to clinical trials, although with mixed results. The development of GSM's continues to as a potentially safer approach to modulating Aβ production in AD treatment.},
}

@article {pmid39627617,
year = {2024},
author = {Wiersema, AF and Rennenberg, A and Smith, G and Varderidou-Minasian, S and Pasterkamp, RJ},
title = {Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {81},
number = {1},
pages = {479},
pmid = {39627617},
issn = {1420-9071},
support = {XS grant//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; GoALS//Stichting ALS Nederland/ ; TOTALS//Stichting ALS Nederland/ ; MUSALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; MAXOMOD//E-rare3/ ; INTEGRALS//Rare-3/ ; TRIAGE//JPND/ ; },
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Cell Communication ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; MicroRNAs/metabolism/genetics ; Animals ; Biomarkers/metabolism ; Parkinson Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.},
}

Humans
*Extracellular Vesicles/metabolism
*Neurodegenerative Diseases/metabolism/pathology
*Cell Communication
*Amyotrophic Lateral Sclerosis/metabolism/pathology
Alzheimer Disease/metabolism/pathology
MicroRNAs/metabolism/genetics
Animals
Biomarkers/metabolism
Parkinson Disease/metabolism/pathology
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid39627450,
year = {2024},
author = {Leal, CBQS and Zimmer, CGM and Sinatti, VVC and Soares, ES and Poppe, B and de Wiart, AC and Chua, XY and da Silva, RV and Magdesian, MH and Rafii, MS and Buée, L and Bottos, RM},
title = {Effects of the therapeutic correction of U1 snRNP complex on Alzheimer's disease.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {30085},
pmid = {39627450},
issn = {2045-2322},
mesh = {*Alzheimer Disease/metabolism/drug therapy ; Animals ; *Ribonucleoprotein, U1 Small Nuclear/metabolism ; Mice ; Humans ; *tau Proteins/metabolism ; Disease Models, Animal ; Neurons/metabolism ; Amyloid beta-Peptides/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Hippocampus/metabolism ; Male ; },
abstract = {The U1 snRNP complex recognizes pre-mRNA splicing sites in the early stages of spliceosome assembly and suppresses premature cleavage and polyadenylation. Its dysfunction may precede Alzheimer's disease (AD) hallmarks. Here we evaluated the effects of a synthetic single-stranded cDNA (APT20TTMG) that interacts with U1 snRNP, in iPSC-derived neurons from a donor diagnosed with AD and in the SAMP8 mouse model. APT20TTMG effectively binds to U1 snRNP, specifically decreasing TAU in AD neurons, without changing mitochondrial activity or glutamate. Treatment enhanced neuronal electrical activity, promoted an enrichment of differentially expressed genes related to key processes affected by AD. In SAMP8 mice, APT20TTMG reduced insoluble pTAU in the hippocampus, amyloid-beta and GFAP in the cortex, and U1-70 K in both brain regions, without cognitive changes. This study highlights the correction of the U1 snRNP complex as a new target for AD.},
}

*Alzheimer Disease/metabolism/drug therapy
Animals
*Ribonucleoprotein, U1 Small Nuclear/metabolism
Mice
Humans
*tau Proteins/metabolism
Disease Models, Animal
Neurons/metabolism
Amyloid beta-Peptides/metabolism
Induced Pluripotent Stem Cells/metabolism
Hippocampus/metabolism
Male

@article {pmid39626378,
year = {2024},
author = {Yang, H and Byun, MS and Ha, NY and Yang, J and Park, SY and Park, JE and Yi, D and Chang, YT and Jung, WS and Kim, JY and Kim, J and Lee, DY and Bae, H},
title = {A preclinical and phase I clinical study of ex vivo-expanded amyloid beta-specific human regulatory T cells in Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {181},
number = {},
pages = {117721},
doi = {10.1016/j.biopha.2024.117721},
pmid = {39626378},
issn = {1950-6007},
abstract = {INTRODUCTION: Despite advancements in adoptive regulatory T cell (Treg) therapy, its application in Alzheimer's disease (AD) remains constrained by challenges in ex vivo Treg selection and expansion with antigen specificity. Our previous findings demonstrated the bystander suppressive immunomodulatory mechanism of ex vivo expanded amyloid β-specific mouse Tregs in AD models, prompting inquiry into the efficacy of ex vivo expanded human Tregs in AD.

METHODS: We developed an effective ex vivo expansion method for manufacturing amyloid β-specific human Tregs (Aβ-hTreg) and evaluated their safety and efficacy in 3xTg mouse models of AD and a phase 1 clinical trial with six AD patients. The phenotype of Aβ-hTreg was analyzed using single-cell transcriptomics. The clinical trial involved intravenous administration of Aβ-hTreg, with three patients receiving a low dose and three receiving a high dose. Exploratory assessments of effectiveness, including cognitive tasks and functional evaluations, were conducted ninety days post-treatment.

RESULTS: Behavioral spatial learning and memory impairment, neuroinflammatory and amyloid pathology were dramatically ameliorated by single intrathecal administration of ex vivo expanded Aβ-hTreg to 3xTg AD mice. Single cell transcriptomics analysis revealed alterations in five key genes within a cluster of Tregs under antigen-specific manufacturing conditions. In the clinical trial with six AD patients, dose-limiting toxicity was experienced by none of the participants within five days of receiving GMP-grade Aβ-hTreg (VT301), indicating its good tolerability. Although exploratory assessments of effectiveness did not reach statistically significant values among the groups, these findings offer valuable insights for AD treatment and management, guiding the planning of the next phase of clinical trials.

DISCUSSION: This study suggests that hTregs may modulate Alzheimer's disease pathology by suppressing neuroinflammation, while VT301 shows promise as a safe treatment option. However, further research is necessary to confirm its clinical efficacy and optimize treatment strategies.

TRIAL REGISTRATION: Title: A Study of Possibility of Using Regulatory T Cells (VT301) for Treatment of Alzheimer's Disease, ClinicalTrials.gov NCT05016427, Study approval date: Ministry of Food and Drug Safety of the Republic of Korea (MFDS) - August 31st, 2020, Institutional Review Board (IRB) of Seoul National University Hospital, Republic of Korea - September 29th, 2020, The date of first patient enrollment: December 7th, 2020. https://clinicaltrials.gov/study/NCT05016427.},
}

@article {pmid39625718,
year = {2024},
author = {Yang, H and Tan, H and Wen, H and Xin, P and Liu, Y and Deng, Z and Xu, Y and Gao, F and Zhang, L and Ye, Z and Zhang, Z and Chen, Y and Wang, Y and Sun, J and Lam, JWY and Zhao, Z and Kwok, RTK and Qiu, Z and Tang, BZ},
title = {Recent Progress in Nanomedicine for the Diagnosis and Treatment of Alzheimer's Diseases.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.4c11966},
pmid = {39625718},
issn = {1936-086X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that causes memory loss and progressive and permanent deterioration of cognitive function. The most challenging issue in combating AD is its complicated pathogenesis, which includes the deposition of amyloid β (Aβ) plaques, intracellular hyperphosphorylated tau protein, neurofibrillary tangles (NFT), etc. Despite rapid advancements in mechanistic research and drug development for AD, the currently developed drugs only improve cognitive ability and temporarily relieve symptoms but cannot prevent the development of AD. Moreover, the blood-brain barrier (BBB) creates a huge barrier to drug delivery in the brain. Therefore, effective diagnostic tools and treatments are urgently needed. In recent years, nanomedicine has provided opportunities to overcome the challenges and limitations associated with traditional diagnostics or treatments. Various types of nanoparticles (NPs) play an essential role in nanomedicine for the diagnosis and treatment of AD, acting as drug carriers to improve targeting and bioavailability across/bypass the BBB or acting as drugs directly on AD lesions. This review categorizes different types of NPs and summarizes their applications in nanomedicine for the diagnosis and treatment of AD. It also discusses the challenges associated with clinical applications and explores the latest developments and prospects of nanomedicine for AD.},
}

@article {pmid39625499,
year = {2024},
author = {Shao, N and Lu, Q and Ouyang, Z and Yang, P and Wei, T and Wang, J and Cai, B},
title = {Ganoderic acid a alleviates Aβ25-35-induced HT22 cell apoptosis through the ERK/MAPK pathway: a system pharmacology and in vitro experimental validation.},
journal = {Metabolic brain disease},
volume = {40},
number = {1},
pages = {51},
pmid = {39625499},
issn = {1573-7365},
support = {2023xscx096//the Postgraduate Quality Engineering Project in Anhui Province/ ; 2023AH050823//the Key Scientific Research Project of Anhui Provincial Department of Education/ ; 2023rcZD001//the Talent Support Programme in Anhui University of Traditional Chinese Medicine/ ; gxbjZD2022024//the Cultivation Programme for Excellent and Top Talents in Anhui Universities/ ; },
mesh = {*Amyloid beta-Peptides/toxicity ; *Apoptosis/drug effects ; *Peptide Fragments/toxicity ; *MAP Kinase Signaling System/drug effects ; *Lanosterol/analogs & derivatives/pharmacology ; Animals ; *Neuroprotective Agents/pharmacology ; *Network Pharmacology ; *Heptanoic Acids/pharmacology ; Mice ; Alzheimer Disease/drug therapy/metabolism ; Cell Line ; Molecular Docking Simulation ; Oxidative Stress/drug effects ; Triterpenes/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that occurs with aging. Ganoderma lucidum (Curtis.) P. Karst. (G. lucidum) is a traditional medicinal fungus believed to nourish the brain and anti-aging. Ganoderic acid A (GAA), a triterpenoid from G. lucidum, has demonstrated natural neuroprotective effects. This study aims to explore the therapeutic effect and molecular mechanism of GAA on AD. Systematic network pharmacology identified 95 targets, 8 biological functions, and multiple pathways. The results highlighted MAPK family members as core genes, with MAPK1 (ERK2) showing the highest binding affinity to GAA in molecular docking. In vitro experiments revealed that GAA dose-dependently increased the viability of Aβ25-35-injured HT22 cells and inhibited MAPK pathway-related protein expression. Similar to FR180204, 100 µM GAA significantly reversed ERK protein expression, oxidative stress markers, and mitochondrial damage in AD cell model. GAA also downregulated cleaved caspase-3 protein levels, apoptosis rates, Aβ and p-Tau expression by inhibiting the ERK signaling pathway. The therapeutic effect of GAA on AD was predicted and validated through network pharmacology and in vitro experiments. The ability of GAA to inhibit apoptosis via the ERK/MAPK signaling pathway positions it as a promising candidate for AD treatment.},
}

*Amyloid beta-Peptides/toxicity
*Apoptosis/drug effects
*Peptide Fragments/toxicity
*MAP Kinase Signaling System/drug effects
*Lanosterol/analogs & derivatives/pharmacology
Animals
*Neuroprotective Agents/pharmacology
*Network Pharmacology
*Heptanoic Acids/pharmacology
Mice
Alzheimer Disease/drug therapy/metabolism
Cell Line
Molecular Docking Simulation
Oxidative Stress/drug effects
Triterpenes/pharmacology

@article {pmid39625180,
year = {2024},
author = {Wei, Y and Qiao, Z},
title = {Neurologic Music Therapy's Impact on Neurological Disorders.},
journal = {Journal of neuroscience research},
volume = {102},
number = {12},
pages = {e70000},
doi = {10.1002/jnr.70000},
pmid = {39625180},
issn = {1097-4547},
mesh = {*Music Therapy/methods ; Humans ; *Nervous System Diseases/therapy ; Brain/physiopathology/diagnostic imaging ; Neuronal Plasticity/physiology ; Parkinson Disease/therapy ; },
abstract = {Neurologic music therapy (NMT) represents a groundbreaking, interdisciplinary approach that combines the therapeutic properties of music with neuroscientific principles to treat a range of neurological and psychiatric conditions. This interdisciplinary approach, increasingly recognized in clinical and research settings, leverages advances in neuroimaging to explore how music affects the structure and activity of the brain. This review provides an in-depth exploration of the multifaceted effects of NMT on brain function, highlighting its role in promoting neuroplastic changes and enhancing cognitive, emotional and motor functions in diverse patient groups. This review consolidates current knowledge on NMT and provides insights into how music affects brain structure and function and the mechanisms of action. The article then discusses the application and research results of NMT in various diseases such as stroke, Alzheimer's disease and Parkinson's disease. Its potential in personalizing therapeutic interventions and its ability to improve treatment access and effectiveness in various settings are highlighted.},
}

*Music Therapy/methods
Humans
*Nervous System Diseases/therapy
Brain/physiopathology/diagnostic imaging
Neuronal Plasticity/physiology
Parkinson Disease/therapy

@article {pmid39624645,
year = {2024},
author = {Li, X and Wang, P and Qi, S and Zhou, J and Amalraj, J and Wang, J and Ding, Z},
title = {The clinical perspective of circular RNAs in neurodegenerative diseases: potential diagnostic tools and therapeutic targets.},
journal = {Frontiers in cellular neuroscience},
volume = {18},
number = {},
pages = {1470641},
pmid = {39624645},
issn = {1662-5102},
abstract = {Neurodegenerative diseases (NDDs) mostly occur in older demographics. With the average lifespan increasing over time, NDDs are becoming one of the major adverse factors affecting human health and the quality of life. Currently, there are no specific diagnostic methods for NDDs and they are usually diagnosed based on nonspecific clinical symptoms and occasionally by biomarkers, such as β-amyloid (Aβ) for Alzheimer's disease (AD) and a-synuclein (α-syn) for Parkinson's disease, etc. However, it is usually too late for most treatment to startr when the aforementioned criteria become detectable. Circular RNAs (circRNAs) are a type of single-stranded, covalently closed, non-coding RNAs that lack a 5' cap structure and 3' terminal poly-A tail. According to recent research, circRNAs may play a crucial role for the onset and progression of some NDDs. These small RNAs may be potential diagnostic and prognostic markers and therapeutic targets for these diseases. This review will provide a comprehensive overview of the recent advancements of knowledge on the functions and the possible underlying mechanism of circRNAs in the pathogenesis and treatment of NDDs.},
}

@article {pmid39624588,
year = {2025},
author = {Yu, Q and Shi, Y and Wu, Y and Liu, R and Zhang, H and Wu, L and Ding, M},
title = {Magnolol acts as a neurorestorative agent in an Aβ1‑42‑induced mouse model of Alzheimer's disease.},
journal = {Experimental and therapeutic medicine},
volume = {29},
number = {1},
pages = {12},
pmid = {39624588},
issn = {1792-1015},
abstract = {Magnolol may have the potential to alleviate the progression of Alzheimer's disease (AD). The present study was conducted to investigate the broader mechanism of action of magnolol in AD pathogenesis. C57BL/6 mice were randomly divided into five groups (n=6 mice/group): i) Control; ii) AD model; iii) 5 mg/kg magnolol + AD model; iv) 10 mg/kg magnolol + AD model; and v) 20 mg/kg magnolol + AD model. A total of 7 days after modeling, the treatment groups were administered different doses of magnolol (5, 10 and 20 mg/kg) by gavage every day, and a Morris water maze test was conducted after 2 months of treatment. The impacts of magnolol on amyloid β (Aβ) plaque deposition and neuroinflammation were assessed using Congo red and immunofluorescence staining. Immunofluorescence staining results were supplemented with western blotting and reverse transcription-quantitative PCR to ascertain the role of magnolol in other pivotal pathological mechanisms, including the formation of intracellular neurofibrillary tangles, compromised synaptic plasticity, and astrocyte and microglia activation. Administration of magnolol effectively mitigated cognitive impairment, reduced Aβ plaque deposition and inhibited neuroinflammation in Aβ1-42-induced mice. Moreover, hippocampal levels of tau, phosphorylated (p-)tau, glycogen synthase kinase 3β (GSK3β), p-GSK3β, synaptophysin, brain-derived neurotrophic factor, glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 revealed that magnolol also limited neurofibrillary tangle formation, repaired synaptic plasticity, and inhibited astrocyte and microglia activation. In conclusion, the present findings broaden the current understanding of the mechanisms explaining the neuroprotective effects of magnolol against AD progression. Notably, it may inhibit multiple manifestations of AD, including plaques and neuroinflammation, while also exhibiting the capacity to restore AD-related neurological damage.},
}

@article {pmid39624221,
year = {2024},
author = {Anyanwu G, E and Nwachukwu I, J and Oria S, R and Obasi K, K and Ekwueme E, P and Nto J, N and Anyanwu N, C},
title = {Fisetin attenuates AlCl3-induced neurodegeneration by modulating oxidative stress and inflammatory cytokine release in adult albino wistar rats.},
journal = {Toxicology reports},
volume = {13},
number = {},
pages = {101812},
pmid = {39624221},
issn = {2214-7500},
abstract = {AIM: Natural flavonoids have powerful antioxidant and anti-inflammatory activities against neurodegenerative diseases. Fisetin is a powerful flavonoid that targets a variety of neurological disorders. Aluminum (Al) has been linked to several neurological conditions, such as Parkinsons disease, autism, and Alzheimer's disease (AD). This study was designed to assess the modulatory role of fisetin in reversing oxidative stress and neuroinflammation caused by Aluminum chloride (AlCl3) induced neurological conditions in rats.

METHODS: Adult male Wistar were randomly divided into eight groups of four animals per group. Group 1; the control group received phosphate-buffered saline, group 2 received 100 mg/kg/bodyweight of aluminum chloride, and group 3,4, and 5 received 25, 50, and 75 mg/kg/bodyweight of fisetin respectively for 21 days. Groups 6, 7, and 8 received 25, 50, and 75 mg/kg/bodyweight of fisetin for 14 days followed by 100 mg/kg/bodyweight of aluminum chloride for 7 days respectively. The administration was via the oral route. Following treatment, the rats were euthanized, and biochemical alterations were observed by measuring the serum levels of Glutathione S-Transferase (GST) and Malondialdehyde (MDA) for oxidative stress and Interleukin-6 (IL-6) for neuroinflammation. Furthermore, histopathological evaluations of the thalamus were carried out using routine Hematoxylin and Eosin (H&E) and Cresyl Fast Violet (CFV) techniques while expressions of Glial Fibrillary Acidic Protein (GFAP) for astrocytes, and Ionized Calcium Binding Adapter Molecule 1 (IBA1) for microglia, were examined by immunohistochemical methods.

RESULTS: The findings in the AlCl3 group indicated a rise in lipid peroxidation, decreased antioxidant activity, altered thalamic histomorphology, and increased expression of GFAP and IBA1 markers for astrocytes and microglia, respectively. These effects were mitigated in the Fisetin pretreated groups.

CONCLUSION: These results imply that fisetin can attenuate AlCl3-induced neurodegeneration possibly by mitigating oxidative stress and neuroinflammation.},
}

@article {pmid39623973,
year = {2024},
author = {Levy, B and D'Ambrozio, G},
title = {Stepwise identification of prodromal dementia: Testing a practical model for primary care.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877241297410},
doi = {10.1177/13872877241297410},
pmid = {39623973},
issn = {1875-8908},
abstract = {BACKGROUND: Prodromal dementia is largely underdiagnosed in primary care.

OBJECTIVE: To develop a clinical model for detecting prodromal dementia within the operative boundaries of primary care practice.

METHODS: The study employed the Functional Activities Questionnaire (FAQ) and Montreal Cognitive Assessment (MoCA) to evaluate a "functional-cognitive" step-down screening model, in which the MoCA is administered subsequent to reported symptoms on the FAQ. It classified participants from the Alzheimer's Disease Imaging Initiative to three diagnostic categories: (1) healthy cognition (n = 396), (2) mild cognitive impairment without conversion (n = 430), and (3) prodromal dementia assessed 24 months before diagnosis (n = 164).

RESULTS: Analyses indicated that the step-down model (Model 1) performed significantly better than an alternative model that applied the FAQ as a single measure (Model 2) and compared well with another model that administered both screening measures to all participants (Model 3). Gradient Boosting Trees classifications yielded the following estimations for Model 1/Model 2/ Model 3, respectively: Sensitivity = 0.87/0.77/0.89, Specificity = 0.68/0.47/0.70, PPV = 0.73/0.40/0.75, NVP = 0.84/0.81/0.87, F1 Score = 0.79/0.52/0.81, AUC = 0.78/0.67/0.79.

CONCLUSIONS: These analyses support the proposed model. The study offers algorithms for validated measures, which were developed from a well characterized clinical sample. Their accuracy will likely improve further with new data from diverse clinical settings. These results can serve primary care in a timely manner in light of the recent advances in pharmacological treatment of dementia and the expected increase in demand for screening.},
}

@article {pmid39623809,
year = {2024},
author = {Salama, RM and Yehia, R and Elmongy, NF and Sallam, AA and Abd-Elgalil, MM and Schaalan, MF and Abdel-Mottaleb, MMA and Bazan, LS},
title = {Evaluation of betanin-loaded liposomal nanocarriers in AlCl3-induced Alzheimer's disease in rats: Impact on cognitive function, neurodegeneration, and TREM2/ADAM10 pathways.},
journal = {Archiv der Pharmazie},
volume = {},
number = {},
pages = {e2400641},
doi = {10.1002/ardp.202400641},
pmid = {39623809},
issn = {1521-4184},
support = {//None/ ; },
abstract = {Betanin (BET) has been studied for its therapeutic benefits in various diseases, but its low bioavailability and uncertain brain penetration limit its efficacy. Accordingly, this study aimed to explore BET-loaded liposomal nanocarriers (LPN) as a novel treatment for Alzheimer's disease (AD), focusing on the triggering receptor expressed on myeloid cells 2 (TREM2)/DNAX-activating protein of 12 kDa (DAP12) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways implicated in AD. In an AlCl3-induced AD rat model, 48 male Wistar rats were divided into four groups: control, AlCl3 (50 mg/kg, intraperitoneal), AlCl3+BET (100 mg/kg, per os), and AlCl3+BET LPN (25 mg/kg, intranasally), with treatments administered for 28 days. Morris water maze test and histopathological examination showed that BET LPN-treated rats had improved spatial and learning memory and less hippocampal and cortical degeneration compared with the AlCl3 and oral BET groups. Mechanistically, BET LPN treatment corrected AD biomarkers, increased miR-132 and ADAM10 expression, and reduced oxidative stress, inflammation, and apoptosis. Additionally, BET LPN treatment suppressed the expression of TREM2, DAP12, ERK1/2, and mitogen-activated protein kinase 1/2 (MEK1/2), showing greater improvement than oral BET. These findings suggest that BET LPN enhances cognitive function and neuroprotection in AD by modulating miR-132 and ADAM10 and inhibiting ERK1/2 and TREM2/DAP12 pathways, providing a more effective treatment compared with traditional oral BET administration.},
}

@article {pmid39623797,
year = {2024},
author = {Ding, Q and Zhao, Y and Xi, E and Liu, K and Gao, N and Zhu, G},
title = {Constructing a Metal-Organic Frameworks-Based Long-Acting Sequential Release System for the Treatment of Alzheimer's Disease.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e2402425},
doi = {10.1002/adhm.202402425},
pmid = {39623797},
issn = {2192-2659},
support = {2022YFB3805902//National Key R&D Program of China/ ; 22131004//National Natural Science Foundation of China/ ; U21A20330//National Natural Science Foundation of China/ ; 21975039//National Natural Science Foundation of China/ ; 22077118//National Natural Science Foundation of China/ ; B18012//"111" project/ ; 2412023YQ001//Fundamental Research Funds for the Central Universities, Excellent Youth Team Program/ ; JLSWSRCZX2023-52//Finance Special Project on Medical and Health Talents of the Finance Department of Jilin Province/ ; 2020009//WBE Liver Fibrosis Foundation/ ; YDZJ202401202ZYTS//Jilin Province Science and Technology Development Plan Project/ ; },
abstract = {Due to the unclear pathogenesis of Alzheimer's disease (AD) and the lack of a completely cured medication, AD patients need to take medication in order and on time every day all one's life, which is difficult for severe memory impairment patients to strictly follow on time. Traditional AD drug carriers, such as sugar coating and capsules, rely on dissolution or fragmentation to achieve drug release, which lacks the interaction between drug molecules and carriers, thus they cannot achieve sufficient long-acting and sequential drug release. Herein, Mn-MOF-74, which ligand structure is similar to two antioxidants dihydroquercetin (DHQ) and resveratrol (Res) is chosen as the carrier. Due to the differences in adsorption energy between DHQ/MOF and Res/MOF, the release speed of DHQ is much faster than Res. Therefore, Mn-MOF-74 loaded with DHQ and Res (DR@MOF) showed sequential drug release and a long-term antioxidant effect for ≈72 h, with an efficacy time six times longer than that of vitamin E. In 5×FAD transgenic mice, DR@MOF exhibited excellent capacity in maintaining oxidative balance in the brain, ameliorating spatial learning and memory deficits, and showed the potential of an AD agent for long-acting and sequential treatment.},
}

@article {pmid39623428,
year = {2024},
author = {Power, SK and Venkatesan, S and Qu, S and McLaurin, J and Lambe, EK},
title = {Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer's disease models.},
journal = {Translational neurodegeneration},
volume = {13},
number = {1},
pages = {58},
pmid = {39623428},
issn = {2047-9158},
support = {PRJ153101//Institute of Neurosciences, Mental Health and Addiction/ ; MOP89825//Institute of Neurosciences, Mental Health and Addiction/ ; },
mesh = {*Alzheimer Disease/metabolism/genetics ; Animals ; *Prefrontal Cortex/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; *Receptors, Nicotinic/metabolism/genetics ; Rats ; Signal Transduction/physiology ; Acetylcholine/metabolism ; Pyramidal Cells/metabolism ; Humans ; Rats, Transgenic ; Male ; },
abstract = {BACKGROUND: Cognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine ex vivo electrophysiological evidence for active compensation in Alzheimer's disease (AD) focusing on the cholinergic innervation of layer 6 in prefrontal cortex. Cholinergic pathways are vulnerable to neuropathology in AD and its preclinical models, and their modulation of deep layer prefrontal cortex is essential for attention and executive function.

METHODS: We functionally interrogated cholinergic modulation of prefrontal layer 6 pyramidal neurons in two preclinical models: a compound transgenic AD mouse model that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat model that closely recapitulates the human trajectory of AD. We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling.

RESULTS: In two AD models, we found potentially compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology. To identify the locus of this enhanced cholinergic signal, we dissected key pre- and post-synaptic components with pharmacological strategies. We identified a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons. To probe the additional impact of therapeutic intervention on the adapted circuit, we tested cholinergic and nicotinic-selective pro-cognitive treatments. Inhibition of acetylcholinesterase further enhanced endogenous cholinergic responses but greatly distorted their kinetics. Positive allosteric modulation of nicotinic receptors, by contrast, enhanced endogenous cholinergic responses and retained their rapid kinetics.

CONCLUSIONS: We demonstrate that functional nicotinic upregulation occurs within the prefrontal cortex in two AD models. Promisingly, this nicotinic signal can be further enhanced while preserving its rapid kinetic signature. Taken together, our work suggests that compensatory mechanisms are active within the prefrontal cortex that can be harnessed by nicotinic receptor positive allosteric modulation, highlighting a new direction for cognitive treatment in AD neuropathology.},
}

*Alzheimer Disease/metabolism/genetics
Animals
*Prefrontal Cortex/metabolism
*Disease Models, Animal
*Mice, Transgenic
Mice
*Receptors, Nicotinic/metabolism/genetics
Rats
Signal Transduction/physiology
Acetylcholine/metabolism
Pyramidal Cells/metabolism
Humans
Rats, Transgenic
Male

@article {pmid39622402,
year = {2024},
author = {Zhen, M and Dang, M and Cao, Z and Xia, X and Peng, F and Wang, S and Liu, Y},
title = {Methylated cell-free DNA as a novel biomarker in Alzheimer's disease.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {566},
number = {},
pages = {120069},
doi = {10.1016/j.cca.2024.120069},
pmid = {39622402},
issn = {1873-3492},
abstract = {Due to an aging population, Alzheimer's disease (AD), a neurodegenerative disorder, has affected more than 40 million people worldwide, a figure predicted to significantly increase in the coming decades. Despite much effort to understand AD pathogenesis, effective diagnosis and treatment remain a challenge. However, the development of liquid biopsy including the analysis of cell-free DNA (cfDNA) and methylation thereof has provided an alternative source of investigation to further explore the pathophysiology of AD. Herein, we discuss the research progress to date and highlight clinical applications of methylated cfDNA in AD.},
}

@article {pmid39621206,
year = {2024},
author = {Yuan, Y and Zhao, G and Zhao, Y},
title = {Dysregulation of energy metabolism in Alzheimer's disease.},
journal = {Journal of neurology},
volume = {272},
number = {1},
pages = {2},
pmid = {39621206},
issn = {1432-1459},
support = {81600924//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/metabolism ; Humans ; *Energy Metabolism/physiology ; *Brain/metabolism ; Animals ; Mitochondria/metabolism ; },
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Its etiology and associated mechanisms are still unclear, which largely hinders the development of AD treatment strategies. Many studies have shown that dysregulation of energy metabolism in the brain of AD is closely related to disease development. Dysregulation of brain energy metabolism in AD brain is associated with reduced glucose uptake and utilization, altered insulin signaling pathways, and mitochondrial dysfunction. In this study, we summarized the relevant pathways and mechanisms regarding the dysregulation of energy metabolism in AD. In addition, we highlight the possible role of mitochondrial dysfunction as a central role in the AD process. A deeper understanding of the relationship between energy metabolism dysregulation and AD may provide new insights for understanding learning memory impairment in AD patients and in improving AD prevention and treatment.},
}

*Alzheimer Disease/metabolism
Humans
*Energy Metabolism/physiology
*Brain/metabolism
Animals
Mitochondria/metabolism

@article {pmid39620848,
year = {2024},
author = {Ramanan, VK},
title = {Implementing New Dementia Care Models in Practice.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {30},
number = {6},
pages = {1863-1873},
pmid = {39620848},
issn = {1538-6899},
mesh = {Humans ; *Dementia/therapy/diagnosis ; Alzheimer Disease/therapy/diagnosis ; },
abstract = {Care for patients with Alzheimer disease and related neurodegenerative causes of dementia is in the midst of a transformation. Recent advancements in diagnostics and therapeutics reflect a rapidly evolving knowledge base and represent positive steps for patients and clinicians facing these progressive diseases; however, the complexities of emerging biomarkers and treatment options present challenges that will require systematic adaptations to routine care to facilitate effective incorporation of these options. This article reviews ongoing updates in the assessment and management of neurodegenerative causes of dementia, focusing on practical models for innovation that practices and health care systems can use to implement these new tools. In particular, sustainable adaptation in the field will benefit from a comprehensive approach implemented at local levels, including (1) education of clinicians and communities to refine perceptions about dementia care, (2) multifaceted stakeholder engagement to optimize infrastructure and workflows to the new era, and (3) investments in personnel to address existing and exacerbated gaps.},
}

Humans
*Dementia/therapy/diagnosis
Alzheimer Disease/therapy/diagnosis

@article {pmid39620846,
year = {2024},
author = {Geldmacher, DS},
title = {Treatment of Alzheimer Disease.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {30},
number = {6},
pages = {1823-1844},
pmid = {39620846},
issn = {1538-6899},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Cholinesterase Inhibitors/therapeutic use/administration & dosage ; },
abstract = {OBJECTIVE: Symptom-oriented treatment has been the mainstay of Alzheimer disease (AD) pharmacotherapy for decades. This article reviews the evidence basis for symptomatic treatments for AD and the emerging data on amyloid-lowering therapies with possible disease-slowing effects.

LATEST DEVELOPMENT: Amyloid-lowering monoclonal antibody therapies entered clinical use in 2021. In July 2023, lecanemab became the first of these to gain full US Food and Drug Administration (FDA) approval and limited Medicare payment coverage. Donanemab gained similar approval status in July 2024. The approved agents remove amyloid plaque from the brain and appear to slow clinical disease progression but can produce significant adverse events known as amyloid-related imaging abnormalities with cerebral edema or effusion and with cerebral hemorrhages. Extensive safety monitoring is therefore required, including scheduled MRI scans. Also in 2023, brexpiprazole became the first agent specifically approved by the FDA for agitation associated with AD. Suvorexant, an orexin receptor antagonist, previously was approved for the treatment of insomnia in people with mild and moderate AD.

ESSENTIAL POINTS: There is robust evidence for the use of acetylcholinesterase inhibitors for patients with mild, moderate, and severe dementia due to AD, including outcomes beyond changes in cognitive screening test scores. More limited studies support the use of memantine in moderate and severe stages. These agents have a primary effect of delaying decline in cognition and function and postponing the emergence of adverse behaviors. Pharmacotherapy for behavioral and psychological symptoms is less predictable, and most clinical trials have had negative results. Anti-amyloid therapies provide the first FDA-approved option to alter AD pathology, but an understanding of overall utility and value to patients remains in its infancy.},
}

Humans
*Alzheimer Disease/drug therapy
Cholinesterase Inhibitors/therapeutic use/administration & dosage

@article {pmid39620844,
year = {2024},
author = {Quinn, JF and Gray, NE},
title = {Fluid Biomarkers in Dementia Diagnosis.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {30},
number = {6},
pages = {1790-1800},
pmid = {39620844},
issn = {1538-6899},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Dementia/diagnosis/cerebrospinal fluid ; Alzheimer Disease/diagnosis/cerebrospinal fluid/blood ; Lewy Body Disease/diagnosis/cerebrospinal fluid/blood ; Male ; Female ; Aged ; Middle Aged ; alpha-Synuclein/cerebrospinal fluid/blood ; },
abstract = {OBJECTIVE: This article familiarizes neurologists with the currently available CSF and plasma biomarkers for the diagnosis of dementia and diagnosis-dependent treatment decisions.

LATEST DEVELOPMENTS: For Alzheimer disease, the recent US Food and Drug Administration (FDA) approval of monoclonal antibody therapy has increased the urgency of confirming the pathologic diagnosis with biomarkers before initiating therapy. The new availability of disease-modifying therapies also highlights the need for biomarkers to monitor efficacy over time. Both of these needs have been partially addressed by the emergence of improved blood-based biomarkers for Alzheimer disease. Regarding other forms of dementia, the latest development is a CSF assay for aggregated α-synuclein, which permits the biomarker confirmation of synuclein pathology in Lewy body dementia.

ESSENTIAL POINTS: CSF biomarkers for the diagnosis of Alzheimer disease, Lewy body dementia, and Creutzfeldt-Jakob disease are well established. Blood-based biomarkers for dementia diagnosis are emerging and rapidly evolving. Sensitivity and specificity for diagnosis continue to improve, and they are being incorporated into diagnostic decisions. Fluid biomarkers for monitoring the efficacy of therapy are not yet established. Because serial CSF examinations are impractical, the validation of blood-based biomarkers of disease activity will be critical for addressing this unmet need.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Dementia/diagnosis/cerebrospinal fluid
Alzheimer Disease/diagnosis/cerebrospinal fluid/blood
Lewy Body Disease/diagnosis/cerebrospinal fluid/blood
Male
Female
Aged
Middle Aged
alpha-Synuclein/cerebrospinal fluid/blood

@article {pmid39620843,
year = {2024},
author = {Risacher, SL},
title = {Neuroimaging in Dementia.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {30},
number = {6},
pages = {1761-1789},
pmid = {39620843},
issn = {1538-6899},
mesh = {Humans ; *Neuroimaging/methods ; *Dementia/diagnostic imaging/diagnosis ; Positron-Emission Tomography/methods ; Magnetic Resonance Imaging ; Male ; Alzheimer Disease/diagnostic imaging/diagnosis ; Female ; Aged ; },
abstract = {OBJECTIVE: This article captures the current literature regarding the use of neuroimaging measures to study neurodegenerative diseases, including early- and late-onset Alzheimer disease, vascular cognitive impairment, frontotemporal lobar degeneration disorders, dementia with Lewy bodies, and Parkinson disease dementia. In particular, the article highlights significant recent changes in novel therapeutics now available for the treatment of Alzheimer disease and in defining neurodegenerative disease using biological frameworks. Studies summarized include those using structural and functional MRI (fMRI) techniques, as well as metabolic and molecular emission tomography imaging (ie, positron emission tomography [PET] and single-photon emission computerized tomography [SPECT]).

LATEST DEVELOPMENTS: Neuroimaging measures are considered essential biomarkers for the detection and diagnosis of most neurodegenerative diseases. The recent approval of anti-amyloid antibody therapies has highlighted the importance of MRI and PET techniques in treatment eligibility and monitoring for associated side effects. Given the success of the initial biomarker-based classification system for Alzheimer disease (the amyloid, tau, neurodegeneration [A/T/N] framework), researchers in vascular cognitive impairment have created similar techniques for biomarker-based diagnosis. Further, the A/T/N framework for Alzheimer disease has been updated to include several pathologic targets for biomarker detection.

ESSENTIAL POINTS: Neurodegenerative diseases have a major health impact on millions of patients around the world. Neuroimaging biomarkers are rapidly becoming major diagnostic tools for the detection, monitoring, and treatment of neurodegenerative diseases. This article educates readers about the current literature surrounding the use of neuroimaging tools in neurodegenerative diseases along with recent important developments in the field.},
}

Humans
*Neuroimaging/methods
*Dementia/diagnostic imaging/diagnosis
Positron-Emission Tomography/methods
Magnetic Resonance Imaging
Male
Alzheimer Disease/diagnostic imaging/diagnosis
Female
Aged

@article {pmid39620842,
year = {2024},
author = {Marshall, GA},
title = {Neuropsychiatric Symptoms in Dementia.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {30},
number = {6},
pages = {1744-1760},
pmid = {39620842},
issn = {1538-6899},
mesh = {Humans ; *Dementia/drug therapy ; Aged ; Female ; Male ; Mental Disorders/drug therapy/etiology/diagnosis ; },
abstract = {OBJECTIVE: This article discusses the prevalence, pathophysiology, assessment, and management of neuropsychiatric symptoms in patients with dementia.

LATEST DEVELOPMENTS: There is a growing body of evidence localizing neuropsychiatric symptoms in dementia to frontal circuits in the brain, as well as relating them to pathologic changes seen in different dementias. Although very few medications have been approved by the US Food and Drug Administration (FDA) for the treatment of neuropsychiatric symptoms in dementia, there are more clinical trials showing the benefit of antidepressants, stimulants, and antipsychotics. In line with that trend, in 2023, the FDA approved the use of brexpiprazole, an atypical antipsychotic, for the treatment of agitation in Alzheimer disease dementia.

ESSENTIAL POINTS: Neuropsychiatric symptoms are a core feature of all dementias and often emerge before cognitive symptoms manifest. They are highly clinically significant symptoms that disrupt the lives of patients and care partners and greatly influence the decision to place patients in long-term care facilities. The first line of treatment for neuropsychiatric symptoms in dementia is nonpharmacologic behavioral modification, but clinicians often must supplement this intervention with medications using an empiric approach.},
}

Humans
*Dementia/drug therapy
Aged
Female
Male
Mental Disorders/drug therapy/etiology/diagnosis

@article {pmid39620840,
year = {2024},
author = {Silbert, LC},
title = {Vascular Cognitive Impairment.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {30},
number = {6},
pages = {1699-1725},
pmid = {39620840},
issn = {1538-6899},
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/etiology/diagnosis ; *Dementia, Vascular/physiopathology/diagnosis ; Aged ; Female ; Male ; Cerebrovascular Disorders/complications/physiopathology/diagnosis/diagnostic imaging ; },
abstract = {OBJECTIVE: Vascular cognitive impairment is a major contributor to age-associated cognitive decline, both independently and as a contributor to mixed dementia syndromes. This article reviews the current understanding of how vascular dysfunction contributes to cognitive impairment and dementia risk in older individuals and includes updated diagnostic criteria and treatment recommendations.

LATEST DEVELOPMENTS: Clinical and research criteria have been evolving to more accurately determine the full prevalence of vascular cognitive impairment. The Boston Criteria version 2.0 for cerebral amyloid angiopathy now includes multiple punctate MRI T2 white matter hyperintensities and MR-visible perivascular spaces in addition to previously described T2* hemorrhagic signatures. MR-visible perivascular spaces are associated with both vascular cognitive impairment and Alzheimer disease, potentially linking cerebrovascular dysfunction to neurodegenerative disorders through its role in brain waste clearance. The American Heart Association's goal for cardiovascular health promotion, "Life's Essential 8," has been updated to include sleep health and acknowledges psychological well-being and social determinants of health as fundamental components necessary to achieve optimal cardiovascular health for all adults.

ESSENTIAL POINTS: Vascular cognitive impairment is a common and often underrecognized contributor to cognitive impairment in older individuals, with heterogeneous etiologies requiring individualized treatment strategies. Effective cerebrovascular disease risk factor modification starting in midlife is critical to reducing the risk of Alzheimer disease and related dementias, with the goal of preventing vascular brain injury and maintaining cognitive reserve in the presence of nonvascular age-related brain pathologies.},
}

Humans
*Cognitive Dysfunction/physiopathology/etiology/diagnosis
*Dementia, Vascular/physiopathology/diagnosis
Aged
Female
Male
Cerebrovascular Disorders/complications/physiopathology/diagnosis/diagnostic imaging

@article {pmid39620434,
year = {2024},
author = {Goyal, A and Kumari, A and Verma, A and Chaudhary, V and Agrawal, V and Yadav, HN},
title = {Silent Information Regulator 1/Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Axis: A Promising Target for Parkinson's and Alzheimer's Disease Therapies.},
journal = {Journal of biochemical and molecular toxicology},
volume = {38},
number = {12},
pages = {e70078},
doi = {10.1002/jbt.70078},
pmid = {39620434},
issn = {1099-0461},
support = {//The authors received no specific funding for this work./ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; *Sirtuin 1/metabolism ; *Parkinson Disease/metabolism/drug therapy ; Animals ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; },
abstract = {One of the key challenges in medical research is developing safe medications to treat neurodegenerative disorders. Increased oxidative stress, mitochondrial dysfunction, and neuroinflammation are common features of Alzheimer's disease (AD) and Parkinson's disease (PD). Silent information regulator 1 (SIRT-1), part of the sirtuin family, plays a critical role in various physiological processes by binding to histones and nonhistone proteins. SIRT-1 primarily mitigates oxidative stress and regulates mitochondrial activity by maintaining the deacetylated form of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), ensuring stable PGC-1α levels. Research has shown reduced SIRT-1/PGC-1α expression in AD and PD models. Targeting this pathway presents a promising therapeutic approach for managing AD and PD, potentially leading to disease-modifying treatments and improved outcomes. This review highlights the findings of various studies suggesting that the SIRT-1/PGC-1α pathway promotes mitochondrial biogenesis, synaptic plasticity, and cognitive function, as well as exerts antioxidant, anti-inflammatory, and anti-apoptotic effects, offering a potential method for AD and PD treatment.},
}

*Alzheimer Disease/metabolism/drug therapy
Humans
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
*Sirtuin 1/metabolism
*Parkinson Disease/metabolism/drug therapy
Animals
Oxidative Stress/drug effects
Signal Transduction/drug effects

@article {pmid39620329,
year = {2024},
author = {Jia, D and He, T and Sun, L and Wang, Q and Yu, H},
title = {Molecular Signatures and Clinical Significance of Notch Signaling Pathway in Peripheral Blood of Patients with Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050339307241108101528},
pmid = {39620329},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is the most common neurodegenerative disease, and timely and effective diagnosis is essential for the prevention and treatment of AD. Peripheral blood is readily available, inexpensive, and non-invasive, making it an ideal substrate for screening diagnostic biomarkers.

METHOD: The Notch signaling pathway is closely related to AD, so genes related to the Notch signaling pathway may be candidate diagnostic biomarkers for AD. Here, we have performed an integrated analysis of peripheral blood cells transcriptomics from two AD cohorts (GSE63060: Ctrl = 104, MCI = 80, AD = 145; GSE63061: Ctrl = 134, MCI = 109, AD = 139) to reveal the expression levels of 16 Notch signals involving 100 genes.

RESULT: The results have shown the changes in Notch signaling-related genes to be highly consistent in both AD cohorts. Bioinformatics analysis has found Differentially Expressed Genes (DEGs) related to Notch signaling to mainly play important roles in Alzheimer's disease, the Notch signaling pathway, and the C-type lectin receptor signaling pathway. Multiple machine learning analyses have revealed IKBKB, HDAC2, and PIK3R1 to exhibit good diagnostic value in both AD cohorts and that they may be ideal biomarkers for early diagnosis of AD.

CONCLUSION: This study has provided a comprehensive description of the molecular signatures of the Notch signaling pathway in AD peripheral blood and a potential diagnostic model for AD clinical screening.},
}

@article {pmid39618963,
year = {2024},
author = {Dow, LF and Pathirage, R and Erickson, HE and Amani, E and Ronning, DR and Trippier, PC},
title = {Synthesis and biological characterization of a 17β hydroxysteroid dehydrogenase type 10 (17β-HSD10) inhibitor.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {39618963},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is estimated to affect over 55 million people across the world. Small molecule treatment options are limited to symptom management with no impact on disease progression. The need for new protein targets and small molecule hit compounds is unmet and urgent. Hydroxysteroid 17-β dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme known to bind amyloid beta, a hallmark of AD, and potentiate its toxicity to neurons. Identification of small molecules capable of interacting with 17β-HSD10 may drive drug discovery efforts for AD. The screening compound BCC0100281 (1), was previously identified as an inhibitor of 17β-HSD10. Herein we report the first synthetic access to the hit compound following a convergent pathway starting from simple heterocyclic building blocks. The compound was found to be toxic to 'neuron-like' cells, specifically those of neuroblastoma origin, providing a potential hit compound for cancer drug discovery, wherein the protein is known to be overexpressed. However, assay of synthetic intermediates identified novel scaffolds with effect to rescue amyloid beta-induced cytotoxicity, showcasing the power of organic synthesis and medicinal chemistry to optimize hit compounds.},
}

@article {pmid39618111,
year = {2024},
author = {Lee, JJ and Keener, LC and Phan, TX and Reeder, JE and Wang, S and Considine, CM and Darby, RR},
title = {Distinct Patterns of Socioemotional Dysfunction Relate to Aggressive Versus Nonaggressive Rule-breaking Antisocial Behaviors in Behavioral Variant Frontotemporal Dementia.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {37},
number = {4},
pages = {194-204},
pmid = {39618111},
issn = {1543-3641},
mesh = {Humans ; *Frontotemporal Dementia/psychology ; Male ; Female ; Aged ; *Aggression/psychology ; Middle Aged ; *Alzheimer Disease/psychology/complications ; Social Behavior ; Empathy/physiology ; Emotions/physiology ; Neuropsychological Tests/statistics & numerical data ; },
abstract = {BACKGROUND: Antisocial behaviors occur in up to 91% of individuals with behavioral variant frontotemporal dementia (bvFTD). Prior work has shown that antisocial behaviors can be differentiated into aggressive and nonaggressive rule-breaking behavioral subtypes. Socioemotional dysfunction is common in bvFTD and unique compared to other types of dementia.

OBJECTIVE: To determine whether socioemotional dysfunction relates to general antisocial behaviors in individuals with bvFTD, or whether different types of socioemotional dysfunction relate to aggressive versus rule-breaking behaviors.

METHODS: Informants for 28 participants with bvFTD and 21 participants with Alzheimer disease (AD) completed the Social Behavior Questionnaire (SBQ) and the Interpersonal Reactivity Index (IRI). The SBQ measures the presence and severity of 26 antisocial behaviors, including subscales for aggressive behaviors (SBQ-AGG) and nonaggressive rule-breaking behaviors (SBQ-RB). The IRI measures cognitive and emotional empathy capabilities, including subscales for Empathic Concern (IRI-EC) and Perspective-taking (IRI-PT).

RESULTS: As expected, participants with bvFTD had higher scores on the SBQ in total than participants with AD, as well as on the SBQ-AGG and SBQ-RB separately. Participants with bvFTD had lower scores on the IRI-EC and IRI-PT than participants with AD (P < 0.0001 for all measures). Lower scores on the IRI-PT correlated with higher scores on the SBQ-AGG-but not with higher scores on the SBQ-RB-across the combined group of participants (P = 0.007), and within participants in the bvFTD group (P = 0.01) specifically, after controlling for covariates of age, sex, dementia severity, and IRI-EC scores. Lower scores on the IRI-EC correlated with higher scores on the SBQ-AGG-but not with higher scores on the SBQ-RB-across the combined group of participants (P = 0.02) after controlling for covariates of age, sex, dementia severity, and IRI-PT scores.

CONCLUSION: Our results suggest that socioemotional dysfunction relates to antisocial behaviors in individuals with bvFTD, but that the mechanisms leading to aggressive and rule-breaking behaviors are differentiable, providing meaningful implications for distinct approaches to treatment and prevention.},
}

Humans
*Frontotemporal Dementia/psychology
Male
Female
Aged
*Aggression/psychology
Middle Aged
*Alzheimer Disease/psychology/complications
Social Behavior
Empathy/physiology
Emotions/physiology
Neuropsychological Tests/statistics & numerical data

@article {pmid39617303,
year = {2024},
author = {Lin, G and Yie, SLJ and Guo, S and Li, X and Xu, L},
title = {Clinical evidence of acupuncture for amnestic mild cognitive impairment: a systematic review and meta-analysis of randomized controlled trials.},
journal = {Complementary therapies in medicine},
volume = {},
number = {},
pages = {103114},
doi = {10.1016/j.ctim.2024.103114},
pmid = {39617303},
issn = {1873-6963},
abstract = {BACKGROUND: People with amnestic mild cognitive impairment (aMCI) carry a substantial risk of developing dementia compared to non-amnestic MCI (naMCI). Several previous studies proved the remarkable effectiveness of acupuncture for MCI, but they didn't distinguish between aMCI and naMCI. We conducted this meta-analysis to systematically assess the evidence of the efficacy of acupuncture in this unique population with aMCI.

METHODS: We comprehensively searched nine databases on January 09, 2024, to identify relevant articles estimating the effects of acupuncture for aMCI, and then assessed the risk of bias of the included trials utilizing the RoB 2.0 tool which included the domain of randomization process, deviation from intended interventions, missing outcome data, measurement of the outcome, selection of the reported outcome, and overall bias. The results of this meta-analysis were exhibited with forest plots. Sensitivity analyses were conducted to determine the robustness of the pooled results, and publication bias was estimated by Egger's and Begg's tests. Besides, we also performed subgroup analysis to determine whether there was a difference in therapeutic effects between four weeks and eight weeks of treatment duration. The certainty of the evidence was graded using GRADEpro GDT.

RESULTS: A total of 15 randomized controlled trials (RCTs) involving 908 people with aMCI were included in this study. According to the meta-analysis, acupuncture treatment provided a remarkable improvement in cognitive function as assessed by Mini-Mental State Examination (MD = 1.09, 95%CI [0.86, 1.31], p < 0.00001), Montreal Cognitive Assessment (MD = 0.93, 95%CI [0.80, 1.07], p < 0.00001), Alzheimer's Disease Assessment Scale-Cognitive (MD = 1.00, 95%CI [-1.23, -0.77], p < 0.00001), and P300 latency (MD = -15.40, 95%CI [-23.68, -7.12], p = 0.0003). Subgroup analysis showed evidence that the efficacy of four weeks of acupuncture treatment was consistent with that of eight weeks. Sensitive analyses, Egger's and Begg's tests suggested the pooled results were robust and reliable. The overall quality of the evidence, as appraised by the GRADE criteria, was very low or low for all outcomes.

CONCLUSIONS: The evidence from 15 RCTs demonstrated that acupuncture interventions are effective in ameliorating cognitive function in people with aMCI. There is a need for larger-scale multicenter RCTs using standardised training protocols and more rigorous designs to confirm the conclusions further.

REGISTRATION: This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42023460470.},
}

@article {pmid39617173,
year = {2024},
author = {Silva, RO and Haddad, M and Counil, H and Zaouter, C and Patten, SA and Fulop, T and Ramassamy, C},
title = {Exploring the potential of plasma and adipose mesenchymal stem cell-derived extracellular vesicles as novel platforms for neuroinflammation therapy.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jconrel.2024.11.060},
pmid = {39617173},
issn = {1873-4995},
abstract = {Persistent reactive oxygen species (ROS) and neuroinflammation contribute to the onset and progression of neurodegenerative diseases, underscoring the need for targeted therapeutic strategies to mitigate these effects. Extracellular vesicles (EVs) show promise in drug delivery due to their biocompatibility, ability to cross biological barriers, and and specific interactions with cell and tissue receptors. In this study, we demonstrated that human plasma-derived EVs (pEVs) exhibit higher brain-targeting specificity, while adipose-derived mesenchymal stem cells EVs (ADMSC-EVs) offer regenerative and immunomodulatory properties. We further investigated the potential of these EVs as therapeutic carriers for brain-targeted drug delivery, using Donepezil (DNZ) as the model drug. DNZ, a cholinesterase inhibitor commonly used for Alzheimer's disease (AD), also has neuroprotective and anti-inflammatory properties. The size of EVs used ranged from 50 to 300 nm with a surface charge below -30 mV. Both formulations showed rapid cellular internalization, without toxicity, and the ability to cross the blood-brain barrier (BBB) in a zebrafish model. The have analyzed the anti-inflammatory and antioxidant actions of pEVs-DNZ and ADMSC-EVs-DNZ in the presence of lipopolysaccharide (LPS). ADMSC-EVs significantly reduced the inflammatory mediators released by HMC3 microglial cells while treatment with pEVs-DNZ and ADMSC-EVs-DNZ lowered both phagocytic activity and ROS levels in these cells. In vivo experiments using zebrafish larvae revealed that both EV formulations reduced microglial proliferation and exhibited antioxidant effects. Overall, this study highlights the potential of EVs loaded with DNZ as a novel approach for treating neuroinflammation underlying various neurodegenerative diseases.},
}

@article {pmid39616884,
year = {2024},
author = {Dustin, CM and Shiva, SS and Vazquez, A and Saeed, A and Pascoal, T and Cifuentes-Pagano, E and Pagano, PJ},
title = {NOX2 in Alzheimer's and Parkinson's disease.},
journal = {Redox biology},
volume = {78},
number = {},
pages = {103433},
doi = {10.1016/j.redox.2024.103433},
pmid = {39616884},
issn = {2213-2317},
abstract = {Alzheimer's Disease (AD), and related dementias, represent a growing concern for the worldwide population given the increased numbers of people of advanced age. Marked by significant degradation of neurological tissues and critical processes, in addition to more specific factors such as the presence of amyloid plaques and neurofibrillary tangles in AD, robust discussion is ongoing regarding the precise mechanisms by which these diseases arise. One of the major interests in recent years has been the contribution of reactive oxygen species (ROS) and, particularly, the contribution of the ROS-generating NADPH Oxidase proteins. NADPH Oxidase 2 (NOX2), the prototypical member of the family, represents a particularly interesting target for study given its close association with vascular and inflammatory processes in all tissues, including the brain, and the association of these processes with AD development and progression. In this review, we discuss the most relevant and recent work regarding the contribution of NOX2 to AD progression in neuronal, microglial, and cerebrovascular signaling. Furthermore, we will discuss the most promising NOX2-targeted therapeutics for potential AD management and treatment.},
}

@article {pmid39614969,
year = {2024},
author = {Yamaguchi, T and Sasaki, H and Yatsu, G and Koyama, K and Kinoshita, K},
title = {Meroterpenoids with BACE1-inhibitory activity from the fruiting bodies of Suillus bovinus and Boletinus cavipes.},
journal = {Journal of natural medicines},
volume = {},
number = {},
pages = {},
pmid = {39614969},
issn = {1861-0293},
support = {17K08351//Japan Society for the Promotion of Science/ ; 24K09868//Japan Society for the Promotion of Science/ ; },
abstract = {Alzheimer disease (AD) is the most common type of dementia and accounts for the largest proportion of dementia cases. The amyloid cascade hypothesis is known for the pathogenesis of AD, in which excessive accumulation of amyloid-β (Aβ) leads to the formation of senile plaques and ultimately to AD. Inhibition of β-secretase (BACE1) may contribute to the treatment of AD by suppressing Aβ production. In this study, we isolated and characterized the activity of new and known BACE1-inhibiting compounds from two mushrooms of the Boletales order, Suillus bovinus and Boletinus cavipes, using a BACE1-inhibitory activity-guided separation approach. Three compounds (1-3) were isolated from Suillus bovinus CHCl3 extract and three compounds (4-6) were isolated from Boletinus cavipes CHCl3 extract. Compound 1 was a new compound. The structures were elucidated using MS, IR, and NMR. Compounds 1-6 showed BACE1-inhibitory activity (IC50; 21.2, 17.8, 1.0, 1.6, 23.7, and 22.8 μM, respectively). To examine the structure-activity relationship, we also evaluated the activity of geranylgerniol, farnesol, 2,5-dihydroxy-1,4-benzoquinone and mesaconic acid. These compounds showed no activity, and these results indicate that chain terpenes alone do not show BACE1-inhibitory activity, but only when mesaconic acid or a quinone with a hydroxyl group is bound. In addition, the mode of inhibition of 2 and 3 were competitive and 4 was uncompetitive inhibition, respectively, as determined by analysis of Lineweaver-Burk and Dixon plots.},
}

@article {pmid39614747,
year = {2024},
author = {Shaw, LM and Korecka, M and Lee, EB and Cousins, KAQ and Vanderstichele, H and Schindler, SE and Tosun, D and DeMarco, ML and Brylska, M and Wan, Y and Burnham, S and Sciulli, A and Vulaj, A and Tropea, TF and Chen-Plotkin, A and Wolk, DA and , },
title = {ADNI Biomarker Core: A review of progress since 2004 and future challenges.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.14264},
pmid = {39614747},
issn = {1552-5279},
support = {//Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //the Foundation for the National Institutes of Healt/ ; },
abstract = {BACKGROUND: We describe the Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core major activities from October 2004 to March 2024, including biobanking ADNI cerebrospinal fluid (CSF), plasma, and serum biofluid samples, biofluid analyses for Alzheimer's disease (AD) biomarkers in the Biomarker Core and various non-ADNI laboratories, and continuous assessments of pre-analytics.

RESULTS: Validated immunoassay and mass spectrometry-based assays were performed in CSF with a shift to plasma, a more accessible biofluid, as qualified assays became available. Performance comparisons across different CSF and plasma AD biomarker measurement platforms have enriched substantially the ADNI participant database enabling method performance determinations for AD pathology detection and longitudinal assessments of disease progression.

DISCUSSION: Close collaboration with academic and industrial partners in the validation and implementation of AD biomarkers for early detection of disease pathology in treatment trials and ultimately in clinical practice is a key factor for the success of the work done in the Biomarker Core.

HIGHLIGHTS: Describe ADNI Biomarker Core biobanking and sample distribution from 2007 to 2024. Discuss validated mass spectrometry and immunoassay methods for ADNI biofluid analyses. Review collaborations with academic and industrial partners to detect AD and progression. Discuss major challenges, and progress to date, for co-pathology detection. Implementation in the ATN scheme: co-pathology and modeling disease progression.},
}

@article {pmid39614308,
year = {2024},
author = {Banna, HU and Slayo, M and Armitage, JA and Del Rosal, B and Vocale, L and Spencer, SJ},
title = {Imaging the eye as a window to brain health: frontier approaches and future directions.},
journal = {Journal of neuroinflammation},
volume = {21},
number = {1},
pages = {309},
pmid = {39614308},
issn = {1742-2094},
support = {DP230101331//ARC/ ; DP230101331//ARC/ ; JPND2021-650-233//JPND/ ; 2019196//NHMRC/ ; },
mesh = {Humans ; Animals ; *Brain/diagnostic imaging/pathology ; Retina/diagnostic imaging/pathology ; Brain Diseases/pathology/diagnostic imaging/diagnosis ; Optical Imaging/methods/trends ; },
abstract = {Recent years have seen significant advances in diagnostic testing of central nervous system (CNS) function and disease. However, there remain challenges in developing a comprehensive suite of non- or minimally invasive assays of neural health and disease progression. Due to the direct connection with the CNS, structural changes in the neural retina, retinal vasculature and morphological changes in retinal immune cells can occur in parallel with disease conditions in the brain. The retina can also, uniquely, be assessed directly and non-invasively. For these reasons, the retina may prove to be an important "window" for revealing and understanding brain disease. In this review, we discuss the gross anatomy of the eye, focusing on the sensory and non-sensory cells of the retina, especially microglia, that lend themselves to diagnosing brain disease by imaging the retina. We include a history of ocular imaging to describe the different imaging approaches undertaken in the past and outline current and emerging technologies including retinal autofluorescence imaging, Raman spectroscopy, and artificial intelligence image analysis. These new technologies show promising potential for retinal imaging to be used as a tool for the diagnosis of brain disorders such as Alzheimer's disease and others and the assessment of treatment success.},
}

Humans
Animals
*Brain/diagnostic imaging/pathology
Retina/diagnostic imaging/pathology
Brain Diseases/pathology/diagnostic imaging/diagnosis
Optical Imaging/methods/trends

@article {pmid39613776,
year = {2024},
author = {Hansen, LS and Carstensen, MH and Henney, MA and Nguyen, NM and Thorning-Schmidt, MW and Broeng, J and Petersen, PM and Andersen, TS},
title = {Light-based gamma entrainment with novel invisible spectral flicker stimuli.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {29747},
pmid = {39613776},
issn = {2045-2322},
support = {501100005192//Danmarks Tekniske Universitet (Technical University of Denmark)/ ; 1044-00177A//Innovationsfonden (Innovation Fund Denmark)/ ; },
mesh = {Humans ; Male ; Female ; *Evoked Potentials, Visual/physiology ; *Photic Stimulation/methods ; Adult ; Light ; Alzheimer Disease/physiopathology ; Young Adult ; Electroencephalography ; Gamma Rhythm/physiology ; },
abstract = {Light-based gamma entrainment using sensory stimuli (GENUS) shows considerable potential for the treatment of Alzheimer's disease (AD) in both animal and human models. While the clinical efficacy of GENUS for AD is paramount, its effectiveness will eventually also rely on the barrier to treatment adherence imposed by the discomfort of gazing at luminance flickering (LF) light. Currently, there have been few attempts to improve the comfort of GENUS. Here we investigate if Invisible spectral flicker (ISF), a novel type of light-based 40 Hz GENUS for which the flicker is almost imperceptible, can be used as a more comfortable option. We found that whereas ISF, LF, and chromatic flicker (CF) all produce a 40 Hz steady-state visually evoked potential (SSVEP), ISF scores significantly better on measures of comfort and perceived flicker. We also demonstrate that, while there is a trend towards a lower SSVEP response, reducing the stimulation brightness has no significant effect on the 40 Hz SSVEP or perceived flicker, though it significantly improves comfort. Finally, there is a slight decrease in the 40 Hz SSVEP response when stimulating with ISF from increasingly peripheral angles. This may ease the discomfort of GENUS treatment by freeing patients from gazing directly at the light.},
}

Humans
Male
Female
*Evoked Potentials, Visual/physiology
*Photic Stimulation/methods
Adult
Light
Alzheimer Disease/physiopathology
Young Adult
Electroencephalography
Gamma Rhythm/physiology

@article {pmid39611008,
year = {2024},
author = {Lavanya, M and Namasivayam, SKR and Priyanka, S and Abiraamavalli, T},
title = {Microencapsulation and nanoencapsulation of bacterial probiotics: new frontiers in Alzheimer's disease treatment.},
journal = {3 Biotech},
volume = {14},
number = {12},
pages = {313},
pmid = {39611008},
issn = {2190-572X},
abstract = {Alzheimer's disease, a progressive neurodegenerative disorder marked by cognitive decline, affects millions worldwide. The presence of amyloid plaques and neurofibrillary tangles in the brain is the key pathological feature, leading to neuronal dysfunction and cell death. Current treatment options include pharmacological approaches such as cholinesterase inhibitors, as well as non-pharmacological strategies like cognitive training and lifestyle modifications. Recently, the potential role of probiotics, particularly strains, such as Lactobacillus and Bifidobacterium, in managing neurodegenerative diseases through the gut-brain axis has garnered significant attention. Probiotics can modulate inflammation, produce neurotransmitters, and support neuronal health, potentially slowing disease progression and alleviating symptoms, such as stress and anxiety. Optimizing the pharmacotherapeutic effects of probiotics is critical and involves advanced formulation techniques, such as microencapsulation and nanoencapsulation. Microencapsulation employs natural or synthetic polymers to protect probiotic cells, enhancing their viability and stability against environmental stressors. Methods like extrusion, emulsion, and spray-drying are used to create microcapsules suited for various applications. Nanoencapsulation, on the other hand, operates at the nanoscale, utilizing polymeric or lipid-based nanoparticles to improve the bioavailability and shelf life of probiotics. Techniques, such as nanoprecipitation and emulsification, are employed to ensure stable nanocapsule formation, thereby augmenting the therapeutic potential of probiotics as nutraceutical agents. This study delves into the essential formulation aspects of microencapsulation and nanoencapsulation for beneficial probiotic strains, aimed at managing Alzheimer's disease by optimizing the gut-brain axis. The insights gained from these advanced techniques promise to enhance probiotic delivery efficacy, potentially leading to improved health outcomes for patients suffering from neurodegenerative disorders.},
}

@article {pmid39610298,
year = {2024},
author = {Juday, TR and Holub, A and Mattke, S and Betts, KA and Kitchen, SA and Liu, H and Batrla, R and Frech, FH and Khachaturian, AS},
title = {Real-world diagnostic, referral, and treatment patterns in early Alzheimer's disease among community-based practices in the United States.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877241297128},
doi = {10.1177/13872877241297128},
pmid = {39610298},
issn = {1875-8908},
abstract = {BACKGROUND: Over 90% of individuals with mild cognitive impairment (MCI) may not receive a timely diagnosis. Understanding community-based practice patterns, where most individuals are seen, is critical to improving patient care.

OBJECTIVE: To understand how patients with MCI and mild dementia due to Alzheimer's disease (AD) are diagnosed and managed in community-based settings, including the use of clinical and cognitive assessments, referrals to dementia-related specialties, and receipt of treatment.

METHODS: This observational study recruited community-based primary care physicians (PCPs) (N = 177) and neurologists (N = 147) in August-September 2023, through a verified physician panel with broad geographic representation across the US. Physicians abstracted medical chart data from patients diagnosed with MCI or mild AD within the previous two years. Data collected included use of neurocognitive assessments, biomarker and structural imagine tests, referrals, and treatments. Descriptive statistics were used.

RESULTS: Medical records for 817 MCI and 467 mild AD patients were abstracted. The mean age was 70.2 years, 56.4% were female, and 67.2% were White. Symptoms were commonly reported by a family member (67.2%). Nearly 1 in 6 patients did not receive any neurocognitive assessments (16.1%), and nearly 1 in 4 did not receive a structural imaging or AD-specific biomarker test (23.7%). AD-specific biomarker tests were more common among patients aged ≥65 (87.1% versus 75.3%; p < 0.05). Less than 1 in 4 patients were referred for cognitive/behavioral concerns.

CONCLUSIONS: As the diagnostic and treatment landscape changes, education on symptom recognition, and physician training on new technologies may facilitate timely diagnoses and improve patient outcomes.},
}

@article {pmid39610292,
year = {2024},
author = {Lam, A and D'Rozario, AL and Kong, S and Ireland, C and Mowszowski, L and LaMonica, HM and Phillips, CL and Hoyos, CM and Grunstein, RR and Naismith, SL},
title = {Screening for obstructive sleep apnea in the memory clinic: A comparison of questionnaires, pulse oximetry, and polysomnography.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877241299458},
doi = {10.1177/13872877241299458},
pmid = {39610292},
issn = {1875-8908},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent among older adults and has been associated with cognitive decline and dementia risk. The suitability of screening tools for detecting OSA in memory clinic settings is unclear.

OBJECTIVE: To evaluate the utility and validity of the STOP-Bang questionnaire (SBQ) and pulse oximeter as a screening tool, compared to gold-standard polysomnography (PSG) in older adults attending a memory clinic.

METHODS: Participants aged over 50 with new onset cognitive/mood concerns attended a memory clinic, then completed the SBQ, oximetry, and PSG. The SBQ and oximetry's accuracy in detecting moderate-severe and severe OSA was evaluated using receiver operating curves. Intraclass correlation and Bland-Altman plots compared the oximeter's adjusted oxygen desaturation index (ODI-Ox) and PSG's apnea-hypopnea index (AHI-PSG).

RESULTS: Of 194 participants (mean age = 65.6, 64 males) who completed PSG, 184 completed the SBQ, and 138 completed oximetry. SBQ demonstrated limited performance for moderate-severe OSA (sensitivity = 52%, specificity = 62%, AUC = 0.600) and severe OSA (sensitivity = 18%, specificity = 87%, AUC = 0.577). Oximetry was satisfactory for moderate-severe OSA (sensitivity = 67%, specificity = 73%, AUC = 0.769) and severe OSA (sensitivity = 50%, specificity = 88%, AUC = 0.730). The diagnostic performance was improved with new cut-offs at ODI-Ox ≥ 11 for AHI-PSG ≥ 15 and ODI-Ox ≥ 20 for AHI-PSG ≥ 30. Bland-Altman plots and intraclass correlation indicated acceptable agreement for oximetry.

CONCLUSIONS: The findings suggest that while the SBQ may be unsuitable to detect moderate or severe OSA for older adults with cognitive impairment, oximetry may be a viable screening tool. Given OSA treatment can optimize sleep and may slow cognitive decline, routine screening for OSA should be part of memory clinic assessments.},
}

@article {pmid35894460,
year = {2022},
author = {Wang, Y and Han, B},
title = {Dulaglutide Alleviates Alzheimer's Disease by Regulating Microglial Polarization and Neurogenic Activity.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/1386207325666220726163514},
pmid = {35894460},
issn = {1875-5402},
abstract = {BACKGROUND: Increasing research has proved that microglial activation, polarization, and inflammatory response in the brain affect the pathology of Alzheimer's disease. Hence, employing reagents targeted to microglial functions to optimize the brain microenvironment may become a promising therapeutic method for Alzheimer's disease.

METHODS: The phagocytosis and clearance of Aβ1-42 were detected using western blot and immunofluorescence assay. The cell viability was determined via 3-(4, 5-Dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide (MTT) or cell counting kit-8 (CCK-8) assay. The load of proinflammation, in addition to anti-inflammation factors, was measured through an enzyme-linked immunosorbent (ELISA) assay. Flow cytometry was employed to estimate the apoptotic cells. The protein level related to microglial polarization and neuronal injury was detected via western blot. The length of the neuronal synapse was investigated using an immunofluorescence assay.

RESULTS: Dulaglutide significantly promoted microglia to phagocytose and removed the Aβ plague. Additionally, dulaglutide treatment inhibited the production of pro-inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin -1β, and IL-6, whereas it increased the load of antiinflammatory molecules, such as IL-10 affected by Aβ1-42 exposure. Further investigation verified that Aβ1-42 down-regulated YM1/2 positive M2 microglial polarization phenotype but up-regulated cyclooxygenase-2 (Cox2) positive M1 microglia. However, treating with dulaglutide effectively counteracted these effects. Moreover, dulaglutide dramatically recovered primary cortical neuron cell viability and inhibited cell apoptosis influenced by Aβ1-42. Furthermore, the dulaglutide also reversed neuronal synapse injury after exposure to Aβ1-42.

CONCLUSION: Altogether, this investigation verified that dulaglutide improved Aβ-induced inflammation and neuronal injury by mediating the activation and polarization of microglia, thereby alleviating Alzheimer's disease efficiently.},
}

@article {pmid39610284,
year = {2024},
author = {Malik, R and Beaton, D and Ahmed, J and Nho, K and Saykin, AJ and Wang, J and Hegele, RA and Finger, E and , },
title = {A DAT1 gene and APOE ε4 interaction is associated with apathy and structural brain changes in mild cognitive impairment and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877241299785},
doi = {10.1177/13872877241299785},
pmid = {39610284},
issn = {1875-8908},
abstract = {BACKGROUND: Apathy in patients with Alzheimer's disease (AD) is associated with significant morbidity and is often one of the first neuropsychiatric symptoms to present in mild cognitive impairment (MCI). Apathy is associated with accelerated cognitive decline and atrophy in fronto-striatal regions of the brain. Previous work has shown a link between apathy and the APOE gene in the context of AD, as the APOE ε4 allele is already known to be associated with the onset of AD. However, other genetic associations with apathy are largely unexplored.

OBJECTIVE: To examine whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with MCI and AD.

METHODS: In a sample of individuals with AD (n = 266), MCI (n = 518), and cognitively normal controls (n = 378), a partial least squares correspondence analysis modeled interactions between single nucleotide polymorphisms, structural whole-brain imaging variables, and apathy.

RESULTS: An interaction was found between apathy, the possession of an APOE ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and regional brain atrophy. This interaction was closely linked to the MCI and AD groups.

CONCLUSIONS: The results point to an association of a dopaminergic genetic marker and apathy in the AD continuum and may inform future design of clinical trials of apathy, as well as new treatment targets.},
}

@article {pmid39610283,
year = {2024},
author = {Engel, MG and Narayan, S and Cui, MH and Branch, CA and Zhang, X and Gandy, SE and Ehrlich, M and Huffman, DM},
title = {Intranasal long R3 insulin-like growth factor-1 treatment promotes amyloid plaque remodeling in cerebral cortex but fails to preserve cognitive function in male 5XFAD mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877241299056},
doi = {10.1177/13872877241299056},
pmid = {39610283},
issn = {1875-8908},
abstract = {BACKGROUND: Insulin-like growth factor-1 (IGF-1) promotes neurogenesis, cell survival, and glial function, making it a promising candidate therapy in Alzheimer's disease (AD).

OBJECTIVE: Long arginine 3-IGF-1 (LR3-IGF-1) is a potent IGF-1 analogue. We sought to determine whether intranasal (IN) LR3 treatment would delay cognitive decline and pathology in 5XFAD mice.

METHODS: Wildtype and 5XFAD male mice were treated for 7 months (3-10 months of age), with IN LR3-IGF-1 or IN Vehicle (Veh) (n = 19-27 mice/group). Behavior, memory, and brain imaging were assessed at 8-9 months of age and tissues collected at 10 months. A comprehensive amyloid-β (Aβ) profile and other pathologic features were conducted and supportive in vitro stimulation studies in BV-2 microglial cells were also performed.

RESULTS: In male 5XFAD mice, IN LR3-IGF-1 treatment improved body composition, but did not significantly alter cognitive symptoms, as assessed by multiple assays. In cortex, LR3 treatment improved some facets of pathology, including a reduction in filamentous plaques, and increase in inert plaques, corresponding with a reduction in low molecular weight Aβ oligomers. In vitro, uptake of Aβ1-42 peptide by BV2 cells was enhanced by LR3-IGF-1, which was also found to promote gene pathways implicated in actin remodeling and endocytosis.

CONCLUSIONS: LR3 promotes favorable effects on Aβ plaque remodeling in cortex of male 5XFAD mice but fails to preserve aspects of behavior or memory. While these data do not support LR3 as a monotherapy per se, they do warrant further investigation into its potential for combinatorial formulations aimed at targeting the complexity of AD.},
}

@article {pmid39610096,
year = {2025},
author = {Pierzynowska, K and Karaszewski, B and Węgrzyn, G},
title = {Genistein: a possible solution for the treatment of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {20},
number = {10},
pages = {2903-2905},
doi = {10.4103/NRR.NRR-D-24-00713},
pmid = {39610096},
issn = {1673-5374},
}

@article {pmid39609333,
year = {2024},
author = {Bhardwaj, V and Kumari, S and Dhapola, R and Sharma, P and Beura, SK and Singh, SK and Vellingiri, B and HariKrishnaReddy, D},
title = {Shedding light on microglial dysregulation in Alzheimer's disease: exploring molecular mechanisms and therapeutic avenues.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {39609333},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) stands out as the foremost prevalent neurodegenerative disorder, characterized by a complex etiology. Various mechanisms have been proposed to elucidate its onset, encompassing amyloid-beta (Aβ) toxicity, tau hyperphosphorylation, oxidative stress and reactive gliosis. The hallmark of AD comprises Aβ and tau aggregation. These misfolded protein aggregates trigger the activation of glial cells, primarily microglia. Microglial cells serve as a major source of inflammatory mediators and their cytotoxic activation has been implicated in various aspects of AD pathology. Activated microglia can adopt M1 or M2 phenotypes, where M1 promotes inflammation by increasing pro-inflammatory cytokines and M2 suppresses inflammation by boosting anti-inflammatory factors. Overexpressed pro-inflammatory cytokines include interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in adjacent brain regions. Furthermore, microglial signaling pathways dysregulated in AD are myeloid differentiation primary-response protein 88 (Myd 88), colony-stimulating factor-1 receptor (CSF1R) and dedicator of cytokinesis 2 (DOCK2), which alter the physiology. Despite numerous findings, the causative role of microglia-mediated neuroinflammation in AD remains elusive. This review concisely explores cellular and molecular mechanisms of activated microglia and their correlation with AD pathogenesis. Additionally, it highlights promising therapeutics targeting microglia modulation, currently undergoing preclinical and clinical studies, for developing effective treatment for AD.},
}

@article {pmid39608999,
year = {2024},
author = {Climacosa, FMM and Anlacan, VMM and Gordovez, FJA and Reyes, JCB and Tabios, IKB and Manalo, RVM and Cruz, JMC and Asis, JLB and Razal, RB and Abaca, MJM and Dacasin, AB and Espiritu, APN and Gapaz, NCLL and Lee Yu, MHL},
title = {Monitoring drug Efficacy through Multi-Omics Research initiative in Alzheimer's Disease (MEMORI-AD): A protocol for a multisite exploratory prospective cohort study on the drug response-related clinical, genetic, microbial and metabolomic signatures in Filipino patients with Alzheimer's disease.},
journal = {BMJ open},
volume = {14},
number = {11},
pages = {e078660},
doi = {10.1136/bmjopen-2023-078660},
pmid = {39608999},
issn = {2044-6055},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; Philippines ; Prospective Studies ; Aged ; Cholinesterase Inhibitors/therapeutic use ; Rivastigmine/therapeutic use ; Donepezil/therapeutic use ; Cross-Sectional Studies ; Memantine/therapeutic use ; Male ; Female ; Metabolomics ; Gastrointestinal Microbiome/drug effects ; Multiomics ; },
abstract = {INTRODUCTION: Dementia is one of the leading causes of disability among older people aged 60 years and above, with majority eventually being diagnosed with Alzheimer's disease (AD). Pharmacological agents approved for dementia include acetylcholinesterase enzyme (AChE) inhibitors like rivastigmine, donepezil and galantamine and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, prescribed as monotherapy or in combination with each other, depending on the severity of disease. There is currently no available study demonstrating the clinical response to these drugs for AD in the Filipino population. Hence, this protocol aims to characterise the clinical, genetic, microbial and metabolic factors associated with drug responses to donepezil, rivastigmine and/or memantine for AD in a cohort of Filipinos with late-onset AD.

METHODS AND ANALYSIS: This protocol involves a multisite descriptive study that will use two study designs: (1) a descriptive, cross-sectional study to characterise the clinical profile of Filipino dementia patients with AD and (2) an exploratory prospective cohort study to investigate drug response-related genetic, gut microbiome and metabolome signatures of a subset of the recruited AD patients. At least 153 patients with mild or moderate AD aged 65 years old and above will be recruited regardless of their treatment status. A subset of these patients (n=60) who meet inclusion and exclusion criteria will be included further in the exploratory cohort study. These patients will be grouped according to their baseline medications and will be observed for treatment response in 6 months. The cognitive, functional and behavioural domains of patients and levels of functioning will be measured using different assessment tools. Drug responses of Filipino patients will then be investigated employing multi-omics technology to characterise genetic variations via whole exome sequencing, gut microbiome profile via shotgun metagenomic sequencing and metabolome profile via liquid chromatography with mass spectrometry.

ETHICS AND DISSEMINATION: The study has received ethical clearance from the Department of Health Single Joint Research Ethics Board (SJREB-2022-15). Results of psychometric scales will be made available to enrolled patients. The study results will be presented at national/international conferences and published in international peer-reviewed scientific journals, and summaries of the results will be provided to the study funders and institutional review boards of the three tertiary referral hospitals.

TRIAL REGISTRATION NUMBER: Philippine Health Research Registry ID PHRR230220-0054116; ClinicalTrials.gov ID NCT05801380.},
}

Humans
*Alzheimer Disease/drug therapy/genetics
Philippines
Prospective Studies
Aged
Cholinesterase Inhibitors/therapeutic use
Rivastigmine/therapeutic use
Donepezil/therapeutic use
Cross-Sectional Studies
Memantine/therapeutic use
Male
Female
Metabolomics
Gastrointestinal Microbiome/drug effects
Multiomics

@article {pmid39608234,
year = {2024},
author = {Hu, T and Li, M and Zhang, X and Gao, Y and Gao, H and Liu, L and Zuo, A and Wang, Y and Guo, J and Zheng, Y},
title = {Combination of mass spectrometry analysis and bioinformatic analysis for characterizing anti-inflammation active components from Boschniakia rossica and the targets.},
journal = {Journal of chromatography. A},
volume = {1739},
number = {},
pages = {465544},
doi = {10.1016/j.chroma.2024.465544},
pmid = {39608234},
issn = {1873-3778},
abstract = {Alzheimer's disease (AD), a demonstrativeness disease with insidious onset, has become an important public health problem worldwide and is the fifth leading cause of death in the world. Boschniakia rossica (BR) has been used to treat age-related diseases, especially AD in China for centuries, but the material basis and mechanism are unclear. Here, we investigated the effective components and the mechanism of BR in the treatment of AD. The therapeutic effect of BR was verified through pathological and behavioral studies of AD rat model. BR can significantly increase the number of nerve cells in the hippocampus and improve the study and memory ability of AD rats. Subsequently, the active composition and the potential targets of BR were explored by UPLC-Q-Orbitrap-HRMS and network pharmacology. Ursolic acid, baicalein, and salicylic acid were the potential pharmacodynamic components acted on the phosphatidylinositol 3-kinase (PI3 K)/protein kinase B (AKT) pathway, which was verified by further molecular docking and molecular dynamics simulations. The in vivo and in vitro study revealed that BR treat AD by reducing the neurotoxicity of Aβ25-35 induced nerve cells by regulating PI3K/AKT signaling pathway. Our data strongly support a theoretical basis and methodology for the treatment of AD by BR and a reference for its new drug development.},
}

@article {pmid39607970,
year = {2024},
author = {El-Shiekh, R and Atwa, AM and Elgindy, AM and Ibrahim, KM and Senna, MM and Ebid, N and Mustafa, AM},
title = {Current Perspective and Mechanistic Insights on α-Hederin for the Prevention and Treatment of Several Non-communicable Diseases.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e202402289},
doi = {10.1002/cbdv.202402289},
pmid = {39607970},
issn = {1612-1880},
abstract = {α-Hederin, a naturally occurring compound found in various plant sources, has remarkable properties and therapeutic potential for human health. One notable attribute is its potent anti-inflammatory activity, such as in arthritis, asthma, and inflammatory bowel disease. In addition, it exhibits notable antioxidant effects implicated in the development of chronic diseases, including cardiovascular disorders and certain types of cancer. According to research, it may limit the growth and proliferation of cancer cells, making it a possible candidate for future cancer treatments. Moreover, it is a promising neuroprotective agent and enhances cognitive function, suggesting its potential in the treatment of neurodegenerative illnesses like Alzheimer's and Parkinson's disease. The multifaceted benefits of α-hederin make it an intriguing compound with significant therapeutic implications. As research progresses, exploring its mechanisms of action and clinical applications is warranted. Harnessing the potential of α-hederin may pave the way for innovative treatment strategies and improved outcomes in the battle against various chronic diseases.},
}

@article {pmid39607636,
year = {2024},
author = {Dziewa, M and Złotek, M and Herbet, M and Piątkowska-Chmiel, I},
title = {Molecular and Cellular Foundations of Aging of the Brain: Anti-aging Strategies in Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {44},
number = {1},
pages = {80},
pmid = {39607636},
issn = {1573-6830},
mesh = {*Alzheimer Disease/therapy/pathology/metabolism ; Humans ; *Aging/pathology ; *Brain/pathology/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD) is a condition characterized by the gradual degeneration of the nervous system that poses significant challenges to cognitive function and overall mental health. Given the increasing global life expectancy, there is an urgent need for effective strategies to prevent and manage Alzheimer's disease, with a particular focus on anti-aging interventions. Recent scientific advancements have unveiled several promising strategies for combating Alzheimer's disease (AD), ranging from lifestyle interventions to cutting-edge pharmacological treatments and therapies targeting the underlying biological processes of aging and AD. Regular physical exercise, cognitive engagement, a balanced diet, and social interaction serve as key pillars in maintaining brain health. At the same time, therapies target key pathological mechanisms of AD, such as amyloid-beta accumulation, tau abnormalities, neuroinflammation, mitochondrial dysfunction, and synaptic loss, offering potential breakthroughs in treatment. Moreover, cutting-edge innovations such as gene therapy, stem cell transplantation, and novel drug delivery systems are emerging as potential game-changers in the fight against AD. This review critically evaluates the latest research on anti-aging interventions and their potential in preventing and treating Alzheimer's disease (AD) by exploring the connections between aging mechanisms and AD pathogenesis. It provides a comprehensive analysis of both well-established and emerging strategies, while also identifying key gaps in current knowledge to guide future research efforts.},
}

*Alzheimer Disease/therapy/pathology/metabolism
Humans
*Aging/pathology
*Brain/pathology/metabolism
Animals

@article {pmid39607205,
year = {2024},
author = {Pinho, RA and Muller, AP and Marqueze, LF and Radak, Z and Arida, RM},
title = {Physical exercise-mediated neuroprotective mechanisms in Parkinson's disease, Alzheimer's disease, and epilepsy.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {57},
number = {},
pages = {e14094},
doi = {10.1590/1414-431X2024e14094},
pmid = {39607205},
issn = {1414-431X},
mesh = {Humans ; *Parkinson Disease/therapy/physiopathology ; *Alzheimer Disease/therapy/physiopathology ; *Epilepsy/therapy/physiopathology ; *Exercise/physiology ; Neuroprotection/physiology ; Neuronal Plasticity/physiology ; Exercise Therapy/methods ; },
abstract = {Research suggests that physical exercise is associated with prevention and management of chronic diseases. The influence of physical exercise on brain function and metabolism and the mechanisms involved are well documented in the literature. This review provides a comprehensive overview of the potential implications of physical exercise and the molecular benefits of exercise in Parkinson's disease, Alzheimer's disease, and epilepsy. Here, we present an overview of the effects of exercise on various aspects of metabolism and brain function. To this end, we conducted an extensive literature search of the PubMed, Web of Science, and Google Scholar databases to identify articles published in the past two decades. This review delves into key aspects including the modulation of neuroinflammation, neurotrophic factors, and synaptic plasticity. Moreover, we explored the potential role of exercise in advancing therapeutic strategies for these chronic diseases. In conclusion, the review highlights the importance of regular physical exercise as a complementary non-pharmacological treatment for individuals with neurological disorders such as Alzheimer's, Parkinson's disease, and epilepsy.},
}

Humans
*Parkinson Disease/therapy/physiopathology
*Alzheimer Disease/therapy/physiopathology
*Epilepsy/therapy/physiopathology
*Exercise/physiology
Neuroprotection/physiology
Neuronal Plasticity/physiology
Exercise Therapy/methods

@article {pmid39606633,
year = {2024},
author = {Xiang, Q and Xiang, Y and Liu, Y and Chen, Y and He, Q and Chen, T and Tang, L and He, B and Li, J},
title = {Revealing the potential therapeutic mechanism of Lonicerae Japonicae Flos in Alzheimer's disease: a computational biology approach.},
journal = {Frontiers in medicine},
volume = {11},
number = {},
pages = {1468561},
pmid = {39606633},
issn = {2296-858X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative brain disease without a cure. Lonicerae Japonicae Flos (LJF), a traditional Chinese herbal medicine, possesses a neuroprotective effect, but its mechanisms for AD are not well understood. This study aimed to investigate potential targets and constituents of LJF against AD.

METHODS: Network pharmacology and bioinformatics analyses were performed to screen potential compounds and targets. Gene Expression Omnibus (GEO) datasets related to AD patients were used to screen core targets of differential expression. Gene expression profiling interactive analysis (GEPIA) was used to validate the correlation between core target genes and major causative genes of AD. The receiver operating characteristic (ROC) analysis was used to evaluate the predictive efficacy of core targets based on GEO datasets. Molecular docking and dynamics simulation were conducted to analyze the binding affinities of effective compounds with core targets.

RESULTS: Network pharmacology analysis showed that 112 intersection targets were identified. Bioinformatics analysis displayed that 32 putative core targets were identified from 112 intersection targets. Only eight core targets were differentially expressed based on GEO datasets. Finally, six core targets of MAPK8, CTNNB1, NFKB1, EGFR, BCL2, and NFE2L2 were related to AD progression and had good predictive ability based on correlation and ROC analyses. Molecular docking and dynamics simulation analyses elucidated that the component of lignan interacted with EGFR, the component of β-carotene interacted with CTNNB1 and BCL2, the component of β-sitosterol interacted with BCL2, the component of hederagenin interacted with NFKB1, the component of berberine interacted with EGFR and BCL2, and the component of baicalein interacted with NFKB1, EGFR and BCL2.

CONCLUSION: Through a comprehensive analysis, this study revealed that six core targets (MAPK8, CTNNB1, NFKB1, EGFR, BCL2, and NFE2L2) and six practical components (lignan, β-carotene, β-sitosterol, hederagenin, berberine, and baicalein) were involved in the mechanism of action of LJF against AD. Our work demonstrated that LJF effectively treats AD through its multi-component and multi-target properties. The findings of this study will establish a theoretical basis for the expanded application of LJF in AD treatment and, hopefully, can guide more advanced experimental research in the future.},
}

@article {pmid39606415,
year = {2024},
author = {Jemimah, S and Abuhantash, F and AlShehhi, A},
title = {c-Triadem: A constrained, explainable deep learning model to identify novel biomarkers in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.11.19.24317595},
pmid = {39606415},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a neurodegenerative disorder that requires early diagnosis for effective management. However, issues with currently available diagnostic biomarkers preclude early diagnosis, necessitating the development of alternative biomarkers and methods, such as blood-based diagnostics. We propose c-Triadem (constrained triple-input Alzheimer's disease model), a novel deep neural network to identify potential blood-based biomarkers for AD and predict mild cognitive impairment (MCI) and AD with high accuracy. The model utilizes genotyping data, gene expression data, and clinical information to predict the disease status of participants, i.e., cognitively normal (CN), MCI, or AD. The nodes of the neural network represent genes and their related pathways, and the edges represent known relationships among the genes and pathways. We trained the model with blood genotyping data, microarray, and clinical features from the Alzheimer's Neuroimaging Disease Initiative (ADNI). We demonstrate that our model's performance is superior to previous models with an AUC of 97% and accuracy of 89%. We then identified the most influential genes and clinical features for prediction using SHapley Additive exPlanations (SHAP). Our SHAP analysis shows that CASP9, LCK, and SDC3 SNPs and PINK1, ATG5, and ubiquitin (UBB, UBC) expression have a higher impact on model performance. Our model has facilitated the identification of potential blood-based genetic markers of DNA damage response and mitophagy in affected regions of the brain. The model can be used for detection and biomarker identification in other related dementias.

AUTHOR SUMMARY: C-Triadem, our novel developed deep neural network, accurately predicts moderate cognitive impairment (MCI) and Alzheimer's disease (AD) while identifying potential blood biomarkers for AD. Current diagnostic methods have limitations, emphasizing the critical need for early AD detection. Our model integrates genetic, gene expression, and clinical data to differentiate among cognitively normal individuals, MCI, and AD cases. Training and validation using Alzheimer's Disease Neuroimaging Initiative (ADNI) data demonstrate superior performance, with a 97% AUC and 89% accuracy, surpassing previous models. SHapley Additive exPlanations (SHAP) analysis highlights key clinical features (e.g., MMSE scores, brain volume) and genes (e.g., CASP9, LCK, SDC3), revealing potential genetic markers and pathways in blood associated with AD. By incorporating Reactome pathways, our approach enhances interpretability, providing insight into the biological context of predictions. In summary, c-Triadem represents a significant advancement in AD diagnostics, enabling earlier and more accurate diagnoses for improved treatment strategies.},
}

@article {pmid39606328,
year = {2024},
author = {Cash, DM and Morgan, KE and O'Connor, A and Veale, TD and Malone, IB and Poole, T and Benzinger, TL and Gordon, BA and Ibanez, L and Li, Y and Llibre-Guerra, JJ and McDade, E and Wang, G and Chhatwal, JP and Day, GS and Huey, E and Jucker, M and Levin, J and Niimi, Y and Noble, JM and Roh, JH and Sánchez-Valle, R and Schofield, PR and Bateman, RJ and Frost, C and Fox, NC and , },
title = {Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.11.12.24316919},
pmid = {39606328},
abstract = {INTRODUCTION: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.

METHODS: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes.

RESULTS: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 22[95%CI 13,46], cortical PIB 32[20,57], CSF p-tau181 58[40,112]) for a four-year trial to have 80% power (5% statistical significance) to detect a 25% reduction in absolute levels of pathology, allowing 40% dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50% reduction in rate of change. Sample sizes ranged from 75-250 (examples precuneus volume: 137[80,284], cortical FDG: 256[100,1208], CDR-SB: 161[102,291]).

DISCUSSION: Despite the rarity of ADAD, clinical trials with feasible sample sizes given the number of cases appear possible.},
}

@article {pmid39605963,
year = {2024},
author = {Ma, K and An, C and Li, M and Zhang, Y and Ren, M and Wei, Y and Xu, W and Wang, R and Bai, Y and Zhang, H and Liu, X and Ji, S and Chen, X and Zhu, K},
title = {Dexmedetomidine Attenuated Neuron Death, Cognitive Decline, and Anxiety-Like Behavior by Inhibiting CXCL2 in CA1 Region of AD Mice.},
journal = {Drug design, development and therapy},
volume = {18},
number = {},
pages = {5351-5365},
pmid = {39605963},
issn = {1177-8881},
mesh = {Animals ; *Dexmedetomidine/pharmacology/administration & dosage ; Mice ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Cognitive Dysfunction/drug therapy ; *Anxiety/drug therapy ; *Chemokine CXCL2/metabolism ; *Neurons/drug effects/metabolism/pathology ; Male ; *Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Cell Death/drug effects ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Mice, Inbred C57BL ; },
abstract = {PURPOSE: β-amyloid overload-induced neuroinflammation and neuronal loss are key pathological changes that occur during the progression of Alzheimer's disease (AD). Dexmedetomidine (Dex) exhibits neuroprotective and anti-inflammatory effects on the nervous system. However, the effect of Dex in AD mice remains unclear, and its neuroprotective regulatory mechanism requires further investigation. This study aimed to reveal how Dex protects against Aβ induced neuropathological changes and behavior dysfunction in AD mice.

METHODS: An AD mouse model was established by the injection of Aβ into the brains of mice, followed by intraperitoneal injection with Dex. CXCL2 overexpression and Yohimbine, a Dex inhibitor, were used to investigate the role of Dex and CXCL2 in the regulation of neuronal loss, cognitive decline, and anxiety-like behavior in AD mice. Behavioral tests were performed to evaluate the cognitive and anxiety status of the mice. Nissl staining and immunofluorescence experiments were conducted to evaluate the status of the hippocampal neurons and astrocytes. qRT-PCR was performed to detect the expression of CXCL2, IL-1β, INOS, SPHK1, Bcl2, IFN-γ, and Caspase 1. The malondialdehyde (MDA) level was detected using an ELISA kit. Terminal TUNEL and Fluoro-Jade C (FJC) staining were used to measure the cell apoptosis rate.

RESULTS: In AD mice, cognitive decline and anxiety-like behaviors were significantly improved by the Dex treatment. The number of neurons was increased in mice in the Dex + AD group compared to those in the AD group, and the number of astrocytes was not significantly different between the two groups. CXCL2, IL-1β, iNOS, and SPHK1 levels were significantly lower in Dex-treated AD mice than those in AD mice. Overloading of CXCL2 or Yohimbine reversed the protective effect of Dex on neuron number and cognitive and anxiety symptoms in AD mice.

CONCLUSION: Our results suggest that Dex exerts neuroprotective effects by downregulating CXCL2. Dex shows potential as a therapeutic drug for AD.},
}

Animals
*Dexmedetomidine/pharmacology/administration & dosage
Mice
*Alzheimer Disease/drug therapy/metabolism/pathology
*Cognitive Dysfunction/drug therapy
*Anxiety/drug therapy
*Chemokine CXCL2/metabolism
*Neurons/drug effects/metabolism/pathology
Male
*Disease Models, Animal
Neuroprotective Agents/pharmacology
Cell Death/drug effects
Amyloid beta-Peptides/metabolism/antagonists & inhibitors
Mice, Inbred C57BL

@article {pmid39605544,
year = {2024},
author = {Li, B and Wang, S and Kerman, B and Hugo, C and Shwab, EK and Shu, C and Chiba-Falek, O and Arvanitakis, Z and Yassine, H},
title = {Microglia States are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.11.18.624141},
pmid = {39605544},
issn = {2692-8205},
abstract = {Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD) but much less is known on the key cell types and pathways driving mechanisms of senescence in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed whole transcriptomic data and utilized single-cell RNA seq integration techniques to unveil the convoluted cell-type-specific and sub-cell-type-state-specific senescence pathologies in AD using both ROSMAP and Sea-AD datasets. We identified that microglia are central components to AD associated senescence phenotypes in ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex of 239 AD and 188 non-AD) among non-neuron cell types. We identified that homeostatic, inflammatory, phagocytic, lipid processing and neuronal surveillance microglia states were associated with AD associated senescence in ROSMAP (152,459 microglia nuclei from six regions of brain tissue of 138 early AD, 79 late AD and 226 control subject) and in Sea-AD (82,486 microglia nuclei of 42 dementia, 42 no dementia and 5 reference subjects) via integrative analysis, which preserves the meaningful biological information of microglia cell states across the datasets. We assessed top senescence associated bioprocesses including mitochondrial, apoptosis, oxidative stress, ER stress, endosomes, and lysosomes systems. Specifically, we found that senescent microglia have altered cholesterol related bioprocesses and dysregulated cholesterol. We discovered three gene co-expression modules, which represent the specific cholesterol related senescence transcriptomic signatures in postmortem brains. To validate these findings, the activation of specific cholesterol associated senescence transcriptomic signatures was assessed using integrative analysis of snRNA-seq data from iMGs (microglia induced from iPSCs) exposed to myelin, Abeta, and synaptosomes (56,454 microglia across two replicates of untreated and four treated groups). In vivo cholesterol associated senescence transcriptomic signatures were preserved and altered after treatment with AD pathological substrates in iMGs. This study provides the first evidence that dysregulation of cholesterol metabolism in microglia is a major driver of senescence pathologies in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to slow down AD progression.},
}

@article {pmid39605436,
year = {2024},
author = {Rahman, MT and Saeed, F and Bozdag, S and , },
title = {Identifying Alzheimer's disease-associated genes using PhenoGeneRanker.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.11.12.623269},
pmid = {39605436},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a neurogenerative disease that affects millions worldwide with no effective treatment. Several studies have been conducted to decipher to genomic underpinnings of AD. Due to its complex nature, many genes have been found to be associated with AD. Despite these findings, the pathophysiology of the disease is still elusive. To discover new putative AD-associated genes, in this study, we integrated multimodal gene and phenotype datasets of AD using network biology methods to prioritize potential AD-related genes. We constructed a multiplex heterogeneous network composed of patient and gene similarity networks utilizing phenotypic and omics datasets of AD patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We applied PhenoGeneRanker to traverse this network to discover potential AD-associated genes. To assess the impact of each network layer and seed gene, we also run PhenoGeneRanker on different variants of the network and seed genes. Our results showed that top-ranked genes captured several known AD-related genes and were enriched in Gene Ontology (GO) terms related to AD. We also observed that several top-ranked genes that are not in AD-associated gene list had literature supporting their potential relevance to AD.},
}

@article {pmid39605111,
year = {2024},
author = {Taha, MME and Khalid, A and Elfatih, F and Mohan, S and Sukumaran, SD and Ul-Haq, Z and Aljahdali, IA and Oraibi, O and Oraibi, B and Alfaifi, HA and Alzahrani, AH and Farasani, A and Jerah, AA and Babiker, YOH and Abdelwahab, SI},
title = {Exploring the diverse acetylcholinesterase inhibitory potential of girinimbine: insights from in vitro assays, molecular docking, and simulation studies.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {70},
number = {10},
pages = {154-160},
doi = {10.14715/cmb/2024.70.10.20},
pmid = {39605111},
issn = {1165-158X},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry ; *Molecular Docking Simulation ; *Acetylcholinesterase/chemistry/metabolism ; *Molecular Dynamics Simulation ; Humans ; Tacrine/chemistry/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Protein Binding ; Murraya/chemistry ; },
abstract = {The search for new treatments for Alzheimer's disease (AD) has led to the exploration of plant-based drugs as potential options. Acetylcholinesterase (AChE) inhibitors are widely used as anti-AD medications. This study aimed to investigate the inhibitory mechanism of girinimbine, a constituent of Murraya koenigii, on AChE. AChE inhibition was assessed by in vitro experiments using the modified Ellman method, as well as in silico molecular docking and molecular dynamic simulation. The results were compared to those of the well-known anti-AChE agents tacrine and propidium iodide. Girinimbine, propidium, and tacrine at concentrations of 3.8X10-5M, 1.1x10-5M, and 6.1x10-7M showed percentages of inhibition percentages of 35.6%, 28.2%, and 76.6%, respectively. The docking and molecular dynamics simulation analyses indicated that girinimbine exhibited a higher binding affinity to AChE compared to propidium and tacrine. This finding was further confirmed by the docking, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of rotation analyses. In conclusion, M. koenigii girinimbine shows promise as an acetylcholinesterase inhibitor for Alzheimer's disease. Further research, including in vivo studies and clinical trials, is needed to explore its potential as a plant-based drug candidate for AD treatment.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry
*Molecular Docking Simulation
*Acetylcholinesterase/chemistry/metabolism
*Molecular Dynamics Simulation
Humans
Tacrine/chemistry/pharmacology
Alzheimer Disease/drug therapy/metabolism
Protein Binding
Murraya/chemistry

@article {pmid39604278,
year = {2024},
author = {Rao, S and Forns, J and Danysh, HE and Calingaert, B and Dempsey, C and Aquilina, T and Pathak, S and Anthony, MS and Layton, JB},
title = {Natural history and clinical outcomes in patients with Alzheimer's disease-related psychosis by antipsychotic treatment status in the United States.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877241297361},
doi = {10.1177/13872877241297361},
pmid = {39604278},
issn = {1875-8908},
abstract = {BACKGROUND: While some literature on clinical outcomes in persons with dementia-related psychosis exists, little is known regarding Alzheimer's disease-related psychosis (ADP).

OBJECTIVE: Describe demographic/clinical characteristics of adults with ADP and estimate incidence of clinical events by antipsychotic treatment status.

METHODS: This cohort study identified adults ≥65 years with Alzheimer's disease and incident psychosis (US Medicare database [2013-2018]) and no prior exposure to antipsychotics. Two nonmutually exclusive ADP subcohorts included: patients who initiated treatment with antipsychotic medications (antipsychotic users) and those who remained untreated (antipsychotic nonusers). Baseline characteristics were evaluated before psychosis diagnosis in untreated patients and before antipsychotic initiation in treated patients. Incidence rates were estimated for falls and fractures (composite and separately), seizure/epilepsy (new onset and any), and mortality.

RESULTS: 145,333 ADP antipsychotic nonusers and 49,452 antipsychotic users were identified. Both cohorts had similar baseline demographics; however, antipsychotic users versus nonusers had higher baseline skilled nursing facility use (40.3% and 27.8%), mood (72.7% and 62.1%) and anxiety (70.9% and 57.3%) disorders, falls/fractures (39.5% and 33.8%), urinary tract infections (55.1% and 47.0%), and frailty index scores (76.0% and 69.7%). Crude incidence rates (95% confidence interval)/100 person-years in antipsychotic users and nonusers were 70.0 (68.9-71.2) and 55.8 (55.4-56.1) (falls/fractures composite), 69.0 (67.9-70.1) and 54.9 (54.5-55.2) (falls), 38.6 (38.1-39.0) and 33.0 (32.7-33.2) (mortality), and 45.8 (44.9-46.7) and 54.2 (53.9-54.6) (any seizure/epilepsy).

CONCLUSIONS: Antipsychotic initiators with ADP had a higher burden of some baseline comorbidities; experienced higher incidence of falls, fractures, and mortality; and had lower incidence of seizure/epilepsy than antipsychotic nonusers.},
}

@article {pmid39604076,
year = {2024},
author = {Zheng, W and Shi, X and Chen, Y and Hou, X and Yang, Z and Yao, W and Lv, T and Bai, F},
title = {Comparative efficacy of intermittent theta burst stimulation and high-frequency repetitive transcranial magnetic stimulation in amnestic mild cognitive impairment patients.},
journal = {Cerebral cortex (New York, N.Y. : 1991)},
volume = {34},
number = {11},
pages = {},
doi = {10.1093/cercor/bhae460},
pmid = {39604076},
issn = {1460-2199},
support = {LKZ2023014//Jiangsu Province Senior Health Project/ ; BE2023674//Key Research and Development Program of Jiangsu Province/ ; 82371437//National Natural Science Foundation of China/ ; 2022-LCYG-MS-05//Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University/ ; },
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/therapy ; *Transcranial Magnetic Stimulation/methods ; Male ; Female ; Aged ; *Magnetic Resonance Imaging ; *Theta Rhythm/physiology ; Amnesia/physiopathology/therapy/diagnostic imaging ; Middle Aged ; Treatment Outcome ; Brain/physiopathology/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {Intermittent theta burst stimulation, a derivative of repetitive transcranial magnetic stimulation, has been applied to improve cognitive deficits. However, its efficacy and mechanisms in enhancing cognitive function in patients with amnestic mild cognitive impairment compared with traditional repetitive transcranial magnetic stimulation paradigms remain unclear. This study recruited 48 amnestic mild cognitive impairment patients, assigning them to intermittent theta burst stimulation, repetitive transcranial magnetic stimulation, and sham groups (5 times/wk for 4 wk). Neuropsychological assessments and functional magnetic resonance imaging data were collected pre- and post-treatment. Regarding efficacy, both angular gyrus intermittent theta burst stimulation and repetitive transcranial magnetic stimulation significantly improved general cognitive function and memory compared to the sham group, with no significant difference between the 2 treatment groups. Mechanistically, significant changes in brain activity within the temporoparietal network were observed in both the intermittent theta burst stimulation and repetitive transcranial magnetic stimulation groups, and these changes correlated with improvements in general cognitive and memory functions. Additionally, intermittent theta burst stimulation showed stronger modulation of functional connectivity between the hippocampus, parahippocampal gyrus, and temporal regions compared to repetitive transcranial magnetic stimulation. The intermittent theta burst stimulation and repetitive transcranial magnetic stimulation can improve cognitive function in amnestic mild cognitive impairment patients, but intermittent theta burst stimulation may offer higher efficiency. Intermittent theta burst stimulation and repetitive transcranial magnetic stimulation likely enhance cognitive function, especially memory function, by modulating the temporoparietal network.},
}

Humans
*Cognitive Dysfunction/physiopathology/therapy
*Transcranial Magnetic Stimulation/methods
Male
Female
Aged
*Magnetic Resonance Imaging
*Theta Rhythm/physiology
Amnesia/physiopathology/therapy/diagnostic imaging
Middle Aged
Treatment Outcome
Brain/physiopathology/diagnostic imaging
Neuropsychological Tests

@article {pmid39603510,
year = {2024},
author = {Nath, DK and Lee, Y},
title = {Exploring the multifaceted functions of amyloid precursor protein-like (APPL) in metabolism and memory using Drosophila melanogaster.},
journal = {Molecules and cells},
volume = {},
number = {},
pages = {100163},
doi = {10.1016/j.mocell.2024.100163},
pmid = {39603510},
issn = {0219-1032},
abstract = {Amyloid precursor protein (APP) is a single-pass transmembrane protein abundantly expressed in the central nervous system and implicated in familial Alzheimer's disease (AD), a progressive neurodegenerative disorder that impairs memory. Here, we investigated the role of amyloid precursor protein-like (APPL) using the model organism Drosophila melanogaster. In this study, Appl null mutants exhibited a reduced lifespan under normal conditions and increased triglyceride (TAG) levels, which were mitigated by metformin treatment. Additionally, taste associative memory impairment in Appl[d] mutants suggested APPL's role in memory formation, which was restored by curcumin supplementation. The Appl[d] mutants also displayed reduced climbing ability, which was improved by supplementation with vitamins C (ascorbic acid) and B2 (riboflavin). These findings suggest that APPL is involved in metabolic regulation, cognition, climbing activity, and aging in Drosophila melanogaster.},
}

@article {pmid39603488,
year = {2024},
author = {Wang, Y and Wu, W and Zeng, F and Meng, X and Peng, M and Wang, J and Chen, Z and Liu, W},
title = {The role of kynurenine pathway metabolism mediated by exercise in the microbial-gut-brain axis in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115070},
doi = {10.1016/j.expneurol.2024.115070},
pmid = {39603488},
issn = {1090-2430},
abstract = {In recent years, the role of the microbiome-gut-brain axis in the pathogenesis of Alzheimer's disease (AD) has garnered increasing attention. Specifically, tryptophan metabolism via the kynurenine pathway (KP) plays a crucial regulatory role in this axis. This study reviews how exercise regulates the microbiome-gut-brain axis by influencing kynurenine pathway metabolism, thereby exerting resistance against AD. This paper also discusses how exercise positively impacts AD via the microbiome-gut-brain axis by modulating the endocrine, autonomic nervous, and immune systems. Although the specific mechanisms are not fully understood, research indicates that exercise may optimize tryptophan metabolism by promoting the growth of beneficial microbiota and inhibiting harmful microbiota, producing substances that are beneficial to the nervous system and combating AD. The aim of this review is to provide new perspectives and potential intervention strategies for the prevention and treatment of AD by exploring the links between exercise, KP and the gut-brain axis.},
}

@article {pmid39602866,
year = {2024},
author = {Zhou, W and Chang, Y and Xiao, Q and Deng, Z and Zhang, L and Yuan, Z and Du, Z},
title = {Structural optimization of naturally derived Ar-turmerone, as novel neuroinflammation suppressors effective in an Alzheimer mouse model.},
journal = {Bioorganic & medicinal chemistry},
volume = {117},
number = {},
pages = {118014},
doi = {10.1016/j.bmc.2024.118014},
pmid = {39602866},
issn = {1464-3391},
abstract = {Microglia-mediated neuroinflammation plays a pivotal role in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. The modulation of chronic and sustained inflammatory processes in the brain with small molecules presents a promising therapeutic strategy for these devastating conditions. Aromatic turmerone (ar-turmerone, ART), an active constituent of turmeric essential oil derived from the edible plant Curcuma longa, has shown substantial potential in mitigating neuroinflammatory responses and associated cognitive deficits. Building on our previous work, we sought to discover more potent neuroinflammation suppressors by designing and synthesizing a series of ar-turmerone derivatives to investigate their structure-activity relationships. Microglia-based cellular evaluations revealed that naphthyl-substituted (7c) and N-substituted amides (7a) demonstrated the most pronounced inhibitory effects against NO, TNF-α, and IL-1β release in vitro. Furthermore, in a lipopolysaccharide (LPS)-induced neuroinflammation model of Alzheimer's disease in mice, these two compounds significantly reduced proinflammatory cytokine release, protected neurons from damage, and ameliorated memory impairments and cognitive deficits in Morris water maze tests. This structural optimization of ar-turmerone yielded highly potent anti-neuroinflammatory compounds, which may serve as promising agents for the treatment of neuroinflammation-related neurodegenerative disorders.},
}

@article {pmid39602498,
year = {2024},
author = {Chen, S and Li, R and Liu, Y and Zhang, Z and Fang, M and Huang, S and Li, Y and Geng, L},
title = {Multifunctional Nitrogen-Doped Carbon Dots to Inhibit the Aggregation of Aβ Peptide and Depolymerize the Aβ Fibrils by Modulating Reactive Oxygen Species.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.4c03454},
pmid = {39602498},
issn = {1520-5827},
abstract = {Multifunctional nitrogen-doped carbon dots (N-CDs) were synthesized, and the morphology, composition, and spectral properties of N-CDs were characterized by multiple characterization techniques. The inhibition of β-amyloid (Aβ) peptide aggregation and the destruction of the Aβ fibril structure by N-CDs were also studied. The conformational transition and morphology of Aβ42 in the presence of N-CDs were monitored by far-UV circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM). The results demonstrated that the prepared N-CDs could effectively inhibit Aβ42 peptide aggregation and depolymerize Aβ fibrils. Furthermore, the inhibition and disaggregation mechanism of existing Aβ42 fibrils by N-CDs was studied by electron paramagnetic resonance spectroscopy (EPR). The results showed that the modulation of reactive oxygen species (ROS) by N-CDs and multiple interactions between N-CDs and Aβ42 fibrils played a crucial part in restraining and reducing the aggregation of Aβ42. Our work demonstrates the therapeutic potential of N-CDs in suppressing Aβ42 peptide aggregation and destroying existing Aβ42 fibrils, which provides a new perspective strategy in the treatment of Alzheimer's disease (AD).},
}

@article {pmid39601452,
year = {2024},
author = {Hard, SAAA and Shivakumar, HN and Bafail, DA and Moqbel Redhwan, MA},
title = {Development of in vitro and in vivo evaluation of mucoadhesive in-situ gel for intranasal delivery of vinpocetine.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/1061186X.2024.2433557},
pmid = {39601452},
issn = {1029-2330},
abstract = {Alzheimer's disease (AD), which is marked by gradual neuronal decline and subsequent loss of cognitive functions and memory, poses significant treatment challenges. The present study involved the development, in vitro, and in vivo evaluation of a novel intranasal mucoadhesive in-situ gel of vinpocetine (VIN) with the aim to target the brain. An innovative gel formulation composed of poloxamer 407, HPMC E15 LV, and citric acid as a solubilizer was developed by 2[3] Factorial Design. The developed optimal formulation exhibited favorable rheological properties as it displayed ideal gelation time (31.6 ± 1.52 sec), optimum gelling temperature (32 ± 1.0 °C), enhanced mucoadhesive strength (6622 ± 2.64 dynes/cm[2]), prolonged adhesion (7.22 ± 0.57 hrs) compared with the baseline formulation (F18), and improved drug release in 12 hrs (39.59 ± 1.6%). In vivo, pharmacokinetics revealed a significant increase in Cmax (∼2-fold) and AUC0-t (∼2-fold) in the brain with the in-situ intranasal gel compared to the oral route. In the rat model of AD, in-situ intranasal gel demonstrated significantly greater efficacy (p < 0.001) than oral administration in alleviating AD symptoms as evidenced by behavioral and histological studies. Thus, VIN in-situ gel can be safe and noninvasive for nose-to-brain drug delivery.},
}

@article {pmid39601176,
year = {2024},
author = {Yan, L and Xu, K and Liu, C and Yu, F and Guo, J and Hou, L and Feng, Y and Yang, M and Gong, Q and Qin, D and Qin, M and Wang, Y and Su, H and Lu, Y},
title = {Polymer-Formulated Nerve Growth Factor Shows Effective Therapeutic Efficacy for Cerebral Microinfarcts.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e2412843},
doi = {10.1002/adma.202412843},
pmid = {39601176},
issn = {1521-4095},
support = {2019YFA0903800//National Key R&D Program of China/ ; 81825007//National Natural Science Foundation of China/ ; 52473137//National Natural Science Foundation of China/ ; 52473137//Innovative Research Group Project of the National Natural Science Foundation of China/ ; 005/2023/SKL [SKL-QRCM(UM)-2023-2025]//State Key Laboratory of Quality Research in Chinese Medicine, University of Macau/ ; 0061/2021/A2//Macau Science and Technology Development Fund/ ; ZYGD23011//1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; ZYJC21029//1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; },
abstract = {Cerebral microinfarcts represent the most prevalent form of ischemic brain injury in the elderly, particularly among those suffering from dementia, Alzheimer's disease, and vascular risk factors. Despite their commonality, effective treatments have remained elusive. Herein, a novel treatment utilizing a polymer-formulated nerve growth factor capable of crossing the blood-brain barrier is reported, which effectively reduced oxidative stress and neuronal apoptosis, reshaped microglia polarization at infarct sites, and decreased the overall microinfarct burden, leading to notable improvements in behavioral and cognitive functions in a mouse model. This work provides a promising new avenue for the treatment of cerebral microinfarcts and other neurodegenerative diseases.},
}

@article {pmid39592705,
year = {2024},
author = {Desarkar, P and Vicario, CM and Soltanlou, M},
title = {Non-invasive brain stimulation in research and therapy.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {29334},
pmid = {39592705},
issn = {2045-2322},
abstract = {Since the introduction of transcranial magnetic stimulation (TMS) almost four decades ago, non-invasive brain stimulation (NIBS) techniques have emerged as promising tools to study brain-behaviour relationships in healthy and impaired states with unprecedented precision. Various NIBS techniques, including TMS, transcranial direct current stimulation (tDCS), and emerging methods such as transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) are employed in both research and clinical settings. TMS has gained regulatory approval for treating conditions like major depressive disorder and migraine, while tDCS is showing efficacy in enhancing cognitive functions in various populations. This collection of articles examines key studies, including the modulation of cognitive-motor functions, optimization of light stimulation for Alzheimer’s therapy, and effects on risk-taking behaviour in violent offenders. Notably, the findings suggest that NIBS can effectively influence executive functions and decision-making processes. They highlight the integration of NIBS with neuroimaging techniques, the importance of personalized targeting, and the potential for combined therapeutic approaches. Future directions include addressing methodological challenges and leveraging artificial intelligence to refine treatment protocols. Collectively, these advancements position NIBS as a transformative tool in both neuroscience research and clinical practice, offering new avenues for understanding and treating complex neuropsychiatric conditions.},
}

@article {pmid39600701,
year = {2024},
author = {Moulton, C and Baroni, A and Quagliarini, E and Leone, L and Digiacomo, L and Morotti, M and Caracciolo, G and Podda, MV and Tasciotti, E},
title = {Navigating the nano-bio immune interface: advancements and challenges in CNS nanotherapeutics.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1447567},
pmid = {39600701},
issn = {1664-3224},
mesh = {Humans ; *Nanoparticles ; Animals ; *Central Nervous System/immunology ; Central Nervous System Diseases/immunology/therapy/drug therapy ; Nanomedicine/methods ; },
abstract = {In recent years, significant advancements have been made in utilizing nanoparticles (NPs) to modulate immune responses within the central nervous system (CNS), offering new opportunities for nanotherapeutic interventions in neurological disorders. NPs can serve as carriers for immunomodulatory agents or platforms for delivering nucleic acid-based therapeutics to regulate gene expression and modulate immune responses. Several studies have demonstrated the efficacy of NP-mediated immune modulation in preclinical models of neurological diseases, including multiple sclerosis, stroke, Alzheimer's disease, and Parkinson's disease. While challenges remain, advancements in NPs engineering and design have led to the development of NPs using diverse strategies to overcome these challenges. The nano-bio interface with the immune system is key in the conceptualization of NPs to efficiently act as nanotherapeutics in the CNS. The biomolecular corona plays a pivotal role in dictating NPs behavior and immune recognition within the CNS, giving researchers the opportunity to optimize NPs design and surface modifications to minimize immunogenicity and enhance biocompatibility. Here, we review how NPs interact with the CNS immune system, focusing on immunosurveillance of NPs, NP-induced immune reprogramming and the impact of the biomolecular corona on NPs behavior in CNS immune responses. The integration of NPs into CNS nanotherapeutics offers promising opportunities for addressing the complex challenges of acute and chronic neurological conditions and pathologies, also in the context of preventive and rehabilitative medicine. By harnessing the nano-bio immune interface and understanding the significance of the biomolecular corona, researchers can develop targeted, safe, and effective nanotherapeutic interventions for a wide range of CNS disorders to improve treatment and rehabilitation. These advancements have the potential to revolutionize the treatment landscape of neurological diseases, offering promising solutions for improved patient care and quality of life in the future.},
}

Humans
*Nanoparticles
Animals
*Central Nervous System/immunology
Central Nervous System Diseases/immunology/therapy/drug therapy
Nanomedicine/methods

@article {pmid39600371,
year = {2024},
author = {Wen, J and Zhao, M and Xiao, Y and Li, S and Hu, W},
title = {OATP1A2 mediates Aβ1-42 transport and may be a novel target for the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1443789},
pmid = {39600371},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with an unknown cause. Many studies have suggested that the imbalance between the clearance and accumulation of β-amyloid protein (Aβ) in the brain of AD patients is the main cause of AD development of AD. Meanwhile, drug transporters play a key role in the transport of drugs and endogenous substances in vivo as well as in the development of many diseases. Could they be related to the imbalance between Aβ clearance and accumulation? OATP1A2 is the most abundant subfamily of organic anion transporting polypeptides (OATPs) that transport amphipathic substrates. Its high bilateral expression in brain endothelial cells suggests it plays a crucial role in delivering drugs and neuroactive peptides to brain tissue. Could it also be involved in mediating the production and accumulation of Aβ in the central system? This could lead to an imbalance between Aβ clearance and accumulation, ultimately resulting in AD development. This hypothesis would be bold and novel in the field of science. In this study, we successfully established the OATP1A2-HEK293T transgenic cell model, and found that the uptake of Aβ1-42 by OATP1A2-HEK293T cells was significantly higher than that of NC-HEK293T control cells and human astrocytes by adding different concentrations of Aβ1-42 to the cells of each group, suggesting that OATP1A2 expressed in the human brain is involved in Aβ amyloid protein transport.},
}

@article {pmid39600269,
year = {2024},
author = {Nakashima, M and Suga, N and Fukumoto, A and Yoshikawa, S and Matsuda, S},
title = {Exosomes, Endosomes, and Caveolae as Encouraging Targets with Favorable Gut Microbiota for the Innovative Treatment of Alzheimer's Diseases.},
journal = {Discovery medicine},
volume = {36},
number = {190},
pages = {2132-2142},
doi = {10.24976/Discov.Med.202436190.196},
pmid = {39600269},
issn = {1944-7930},
mesh = {Humans ; *Alzheimer Disease/microbiology/therapy/metabolism/pathology ; *Gastrointestinal Microbiome ; *Endosomes/metabolism ; *Exosomes/metabolism ; *Caveolae/metabolism ; Animals ; Autophagy ; },
abstract = {Neurodegenerative diseases are characterized by progressive damage to specific neuronal cells, resulting in cognitive impairments. Alzheimer's disease is one of the most common types of cognitive impairments. Until recently, strategies that prevent its clinical progression have remained elusive. It has been suggested that oxidative stress, mitochondrial injury, and inflammation might lead to brain cell death in many neurological disorders. Therefore, the identification of effective neuroprotective agents is a research priority, and several autophagy-targeted bioactive compounds are promising candidate therapeutics for the prevention of brain cell damage. Some Alzheimer's disease risk genes expressed within the brain are linked to cholesterol metabolism, lipid transport, endocytosis, exocytosis, and/or caveolae formation, suggesting fruitful therapeutic targets for the treatment of cognitive impairments. Among them, a well-known genetic risk factor for late-onset Alzheimer's disease is allelic variation of the Apolipoprotein E (APOE) genes. APOE proteins may regulate aspects of cellular homeostasis, which is perturbed in the brain in Alzheimer's disease. Interestingly, the Apolipoprotein E ε4 allele (APOE4) protein is related to autophagy and to the biogenesis of caveolae, endosomes, and exosomes, processes which might consequently be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease. Recent research suggests that modification of the diet and/or gut-microbiota could be effective for treatment of various neurodegenerative diseases. Collectively, this research direction has the potential to improve clinical care through disease-modifying treatment strategies with benefits for patients with neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/microbiology/therapy/metabolism/pathology
*Gastrointestinal Microbiome
*Endosomes/metabolism
*Exosomes/metabolism
*Caveolae/metabolism
Animals
Autophagy

@article {pmid39600165,
year = {2024},
author = {Granberg, T and Börjesson Hanson, A and Fällmar, D and Basun, H and Wahlund, LO},
title = {[New Alzheimer's treatments - a need for national preparations and coordination].},
journal = {Lakartidningen},
volume = {121},
number = {},
pages = {},
pmid = {39600165},
issn = {1652-7518},
mesh = {Humans ; *Alzheimer Disease/diagnosis/drug therapy/therapy ; Sweden ; Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; },
abstract = {Approximately 100,000 persons live with Alzheimer's disease in Sweden. As the population ages, the need for diagnostics and disease-modifying treatment grows. Previously available treatments provide moderate symptom relief but do not affect disease progression. New antibody treatments show promising results and are typically well tolerated. However, adverse events include brain edema and hemorrhages, which can be detected early by MRI. These treatments require substantial resources, including increased use of MRI and radiological expertise. The introduction of new therapies will lead to higher regional healthcare costs and demands for specialized diagnostics. Implementing these therapies therefore necessitates national preparation and planning for coordinated and efficient management, addressing the significant societal and economic challenges posed by Alzheimer's disease.},
}

Humans
*Alzheimer Disease/diagnosis/drug therapy/therapy
Sweden
Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects

@article {pmid39599991,
year = {2024},
author = {Hoang, PL and Vuong, Q},
title = {A Comprehensive Review of the Botany, Bioactive Compounds, and Health Benefits of Leptospermum.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e202401335},
doi = {10.1002/cbdv.202401335},
pmid = {39599991},
issn = {1612-1880},
abstract = {There is increasing interest in research and applications of natural bioactive molecules due to the growing demand for functional ingredients from the pharmaceutical, cosmetic, and food industries. A major challenge is finding suitable natural plant resources for the development of functional ingredients. Leptospermum, a genus of the myrtle family (Myrtaceae), is mainly native to Australia. This genus has been traditionally used for the treatment of a range of ailments, such as colds, fever, constipation, diarrhea, skin, inflammation, stomach disorder, internal and external pain. Manuka honey has been produced from the nectar of Leptospermum flowers, and the leaves of these selected species have been used for producing essential oils. Numerous volatiles and non-volatile active molecules have been identified from essential oils and extracts of Leptospermum. Preliminary studies have linked Leptospermum essential oils and extracts with various health promoting properties, such as anti-microbial activity, anti-diabetes, anticancer, and anti-Alzheimer's disease activities, revealing potential applications of Leptospermum as functional ingredients. To provide better understanding on Leptospermum for future research and applications, this review provides brief information on Leptospermum botanical features, outlines volatile and non-volatile active molecules identified from Leptospermum, reviews potential health benefits, and finally proposes trends for future studies on Leptospermum.},
}

@article {pmid39599715,
year = {2024},
author = {An, Y and Cao, Z and Du, Y and Xu, G and Wang, J and Zheng, J and Lu, Y},
title = {Bidirectional Two-Sample, Two-Step Mendelian Randomisation Study Reveals Mediating Role of Gut Microbiota Between Vitamin B Supplementation and Alzheimer's Disease.},
journal = {Nutrients},
volume = {16},
number = {22},
pages = {},
doi = {10.3390/nu16223929},
pmid = {39599715},
issn = {2072-6643},
support = {2022YFA1103602//This research was funded by the National Key Research and Development Program of China/ ; 82473618//the National Natural Science Foundation of China/ ; 92357305//the National Natural Science Foundation of China/ ; 2020QNRC001//the Young Elite Scientists Sponsorship Program by China Association for Science and Technology/ ; 82103811//the National Natural Science Foundation of China/ ; QML20230301//the Beijing Hospitals Authority Youth Programme/ ; },
mesh = {*Alzheimer Disease/microbiology ; *Gastrointestinal Microbiome/drug effects ; Humans ; *Dietary Supplements ; *Mendelian Randomization Analysis ; *Vitamin B Complex/administration & dosage ; Folic Acid/administration & dosage ; Vitamin B 12/administration & dosage ; Bacteria/genetics/classification/drug effects ; },
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a devastating neurodegenerative disorder with a complex aetiology. The aims of this study were to investigate the relationship between vitamin B supplementation and AD risk and to explore the potential mediating effect of the gut microbiota in this relationship.

METHODS: We employed a Mendelian randomisation analysis to examine the association between different vitamin B supplementation modalities (vitamin B6, folic acid, B12, and vitamin B complex tablets) and AD risk. Univariate Mendelian randomisation with inverse-variance weighting was used. Additionally, mediation analyses were conducted to identify the potential mediating effects of 119 known bacterial genera.

RESULTS: The univariate Mendelian randomisation analyses showed no significant direct associations between individual vitamin B supplements or vitamin B complex tablets and AD risk. However, several gut bacterial genera were significantly associated with AD risk. Lachnospiraceae (NK4A136 group), Paraprevotella, Slackia, and Bifidobacterium were associated with reduced AD risk, while Defluviitaleaceae (UCG011), Desulfovibrio, Eubacterium ventriosum group, and Ruminococcaceae UCG-003 were associated with increased AD risk. The mediation analysis revealed that Lachnospiraceae (NK4A136 group), Defluviitaleaceae (UCG011), and Bifidobacterium fully mediated the causal relationships between vitamin B12, B6, and B complex supplementation, respectively, and AD risk.

CONCLUSIONS: This study provides evidence suggesting that certain gut microbiota genera are significantly associated with AD risk and may mediate the relationship between vitamin B supplementation and AD risk. These findings offer new insights into the variable effectiveness of B vitamins in treating neurodegenerative diseases and suggest potential new strategies for AD treatment and prevention.},
}

*Alzheimer Disease/microbiology
*Gastrointestinal Microbiome/drug effects
Humans
*Dietary Supplements
*Mendelian Randomization Analysis
*Vitamin B Complex/administration & dosage
Folic Acid/administration & dosage
Vitamin B 12/administration & dosage
Bacteria/genetics/classification/drug effects

@article {pmid39599527,
year = {2024},
author = {Farrer, TJ and Moore, JD and Chase, M and Gale, SD and Hedges, DW},
title = {Infectious Disease as a Modifiable Risk Factor for Dementia: A Narrative Review.},
journal = {Pathogens (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/pathogens13110974},
pmid = {39599527},
issn = {2076-0817},
abstract = {This narrative review examines infectious diseases as modifiable risk factors for dementia, particularly in the context of an aging global population. As the prevalence of Alzheimer's disease and related dementias is expected to rise, prevention has become increasingly important due to the limited efficacy of current treatments. Emerging evidence links specific infectious diseases to increased dementia risk, possibly through mechanisms like neuroinflammation and disruption to normal cell function. Here, we review findings on how viral and bacterial infections contribute to dementia and explore potentially preventive measures, including vaccinations and antiviral treatments. Studies indicate that vaccinations against influenza, herpes zoster, and hepatitis, as well as antiviral treatments targeting human herpesvirus, could reduce the incidence of dementia. Additionally, non-pharmaceutical interventions during pandemics and in long-term care settings are highlighted as effective strategies for reducing the spread of infectious diseases, potentially lowering dementia risk. Putative mechanisms underlying the protective effects of these interventions suggest that reducing systemic inflammation may be important to their efficacy. While the currently available evidence suggests at best an association between some infectious diseases and dementia, this narrative review emphasizes the need to incorporate infectious disease prevention into broader public health strategies to potentially mitigate the growing burden of dementia. Further research is required to explore these preventive measures across diverse populations and to deepen our understanding of the biological mechanisms involved.},
}

@article {pmid39598763,
year = {2024},
author = {Atanasov, V and Velkova, L and Tancheva, L and Dolashki, A and Kalfin, R and Dolashka, P},
title = {Key Proteins in Rat Cerebral Cortex: Application of Cornu aspersum Extract as a Neuroprotective Agent in Alzheimer's Type Dementia.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {22},
pages = {},
doi = {10.3390/molecules29225375},
pmid = {39598763},
issn = {1420-3049},
support = {Grant KП-06-H73/5-05.12.2023//Bulgarian National Science Fund/ ; },
mesh = {Animals ; *Cerebral Cortex/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; *Neuroprotective Agents/pharmacology/chemistry ; Disease Models, Animal ; Male ; Proteomics/methods ; },
abstract = {Alzheimer's disease (AD) is the most widespread neurodegenerative disorder. Recently, it was found that mucus extract from Cornu aspersum has beneficial effects on memory and cognitive processes in a rat scopolamine model of AD. The present study elucidated the mechanisms of action of standardized mucus snail extract (SE) enriched with a fraction above 20 kDa on Alzheimer-type dementia in rats. Using proteomic analysis on two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) on rat cortex extracts, we compared protein expression in both groups: the first group was treated intraperitoneally with scopolamine (Sco, 2 mg/kg, 11 days) and the second (Sco + SE) group was treated intraperitoneally with Sco (Sco, 2 mg/kg) and protected by SE (0.5 mL/100 g bw) applied daily orally for 11 days. Brain cortex was separated and the expressions of various proteins related to memory and cognitive functions were identified. We found that the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1, Calbindin, Vacuolar ATP synthase catalytic subunit A, Tropomyosin beta chain, 14-3-3 zeta/delta, Kinesin-1 heavy chain, and Stathmin-4 significantly differs in SE-protected rats as compared to dement animals treated only by Sco, and these brain proteins might be potential therapeutic targets for Alzheimer's-type dementia treatment.},
}

Animals
*Cerebral Cortex/metabolism/drug effects
*Alzheimer Disease/drug therapy/metabolism
Rats
*Neuroprotective Agents/pharmacology/chemistry
Disease Models, Animal
Male
Proteomics/methods

@article {pmid39598746,
year = {2024},
author = {Matošević, A and Opsenica, DM and Bartolić, M and Maraković, N and Stoilković, A and Komatović, K and Zandona, A and Žunec, S and Bosak, A},
title = {Derivatives of Amodiaquine as Potent Human Cholinesterases Inhibitors: Implication for Treatment of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {22},
pages = {},
doi = {10.3390/molecules29225357},
pmid = {39598746},
issn = {1420-3049},
support = {IP-2020-02-9343//Croatian Science Foundation/ ; 451-03-66/2024-03/200026 and 451-03-66/2024-03/200168//MESTD of the Republic of Serbia/ ; 7547552//Special Research Program COVID-19/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Humans ; *Alzheimer Disease/drug therapy ; *Amodiaquine/pharmacology/chemistry ; *Acetylcholinesterase/metabolism/chemistry ; *Butyrylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Antioxidants/pharmacology/chemistry/chemical synthesis ; Blood-Brain Barrier/metabolism/drug effects ; Molecular Structure ; },
abstract = {As some previously reported studies have proven that amodiaquine, in addition to its primary antimalarial activity, also has potential for new applications such as the inhibition of cholinesterases, in our study we focused on the evaluation of the influence of different substituents in the aminoquinoline part of the amodiaquine structure on the inhibition of human acetylcholinesterase and butyrylcholinesterase to investigate the possibility for their use as drugs for the treatment of AD. We synthesized a series of amodiaquine derivatives bearing H-, F-, CF3-, NO2-, CN-, CO2H- or CH3O- groups on the aminoquinoline ring, and determined that all of the tested derivatives were very potent inhibitors of both cholinesterases, with inhibition constants (Ki) in the nM and low μM range and with prominent selectivity (up to 300 times) for the inhibition of acetylcholinesterase. All compounds displayed an ability to chelate biometal ions Fe[2+], Zn[2+] and Cu[2+] and an antioxidant power comparable to that of standard antioxidants. Most of the compounds were estimated to be able to cross the blood-brain barrier by passive transport and were nontoxic toward cells that represent the models of individual organs. Considering all these beneficial features, our study has singled out compound 5, the most potent AChE inhibitor with a CH3O- on C(7) position, followed by 6 and 14, compounds without substituent or hydroxyl groups in the C(17) position, respectively, as the most promising compounds from the series which could be considered as potential multi-target drugs for the treatment of AD.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
Humans
*Alzheimer Disease/drug therapy
*Amodiaquine/pharmacology/chemistry
*Acetylcholinesterase/metabolism/chemistry
*Butyrylcholinesterase/metabolism/chemistry
Structure-Activity Relationship
Antioxidants/pharmacology/chemistry/chemical synthesis
Blood-Brain Barrier/metabolism/drug effects
Molecular Structure

@article {pmid39598703,
year = {2024},
author = {Angelova, VT and Stoyanov, BP and Simeonova, R},
title = {New Insights into the Development of Donepezil-Based Hybrid and Natural Molecules as Multi-Target Drug Agents for Alzheimer's Disease Treatment.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {22},
pages = {},
doi = {10.3390/molecules29225314},
pmid = {39598703},
issn = {1420-3049},
support = {KP-06-N63/11; 14.12.2022.//Bulgarian National Science Fund/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Donepezil/therapeutic use/pharmacology/chemistry ; *Biological Products/chemistry/therapeutic use/pharmacology ; Animals ; Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Drug Development ; Drug Design ; },
abstract = {Alzheimer's disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease's progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In this review, we cover hybrid molecules published between 2014 and 2024. We offer an overview of the strategies employed in drug design and approaches that have led to notable improvements and reduced hepatotoxicity. Our aim is to offer insights into the potential development of new Alzheimer's disease drugs. This overview highlights the potential of multi-target drugs featuring heterocycles with N-benzylpiperidine fragments and natural compounds in improving Alzheimer's disease treatment.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Donepezil/therapeutic use/pharmacology/chemistry
*Biological Products/chemistry/therapeutic use/pharmacology
Animals
Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use
Drug Development
Drug Design

@article {pmid39598614,
year = {2024},
author = {Kim, TK and Hong, JM and Kim, J and Kim, KH and Han, SJ and Kim, IC and Oh, H and Jo, DG and Yim, JH},
title = {Therapeutic Potential of Ramalin Derivatives with Enhanced Stability in the Treatment of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {22},
pages = {},
doi = {10.3390/molecules29225223},
pmid = {39598614},
issn = {1420-3049},
support = {RS-2021-KS211513//Ministry of Oceans and Fisheries/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; *tau Proteins/metabolism ; Phosphorylation/drug effects ; Anti-Inflammatory Agents/pharmacology/chemistry/chemical synthesis/therapeutic use ; },
abstract = {Alzheimer's disease (AD) remains a significant public health challenge with limited effective treatment options. Ramalin, a compound derived from Antarctic lichens, has shown potential in the treatment of AD because of its strong antioxidant and anti-inflammatory properties. However, its instability and toxicity have hindered the development of Ramalin as a viable therapeutic agent. The primary objective of this study was to synthesize and evaluate novel Ramalin derivatives with enhanced stabilities and reduced toxic profiles, with the aim of retaining or improving their therapeutic potential against AD. The antioxidant, anti-inflammatory, anti-BACE-1, and anti-tau activities of four synthesized Ramalin derivatives (i.e., RA-Hyd-Me, RA-Hyd-Me-Tol, RA-Sali, and RA-Benzo) were evaluated. These derivatives demonstrated significantly improved stabilities compared to the parent compound, with RA-Sali giving the most promising results. More specifically, RA-Sali exhibited a potent BACE-1 inhibitory activity and effectively reduced tau phosphorylation, a critical factor in AD pathology. Despite exhibiting reduced antioxidant activities compared to the parent compound, these derivatives represent a potential multi-targeted approach for AD treatment, marking a significant step forward in the development of stable and effective AD therapeutics.},
}

*Alzheimer Disease/drug therapy
Humans
*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
*Antioxidants/pharmacology/chemistry/chemical synthesis
*Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism
*tau Proteins/metabolism
Phosphorylation/drug effects
Anti-Inflammatory Agents/pharmacology/chemistry/chemical synthesis/therapeutic use

@article {pmid39598374,
year = {2024},
author = {Li, Y and Fu, J and Wang, H},
title = {Advancements in Targeting Ion Channels for the Treatment of Neurodegenerative Diseases.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {11},
pages = {},
doi = {10.3390/ph17111462},
pmid = {39598374},
issn = {1424-8247},
support = {2023YFF1205500//National Key Research and Development Program of China/ ; 82471465//NSFC/ ; C2024202005//Distinguished Young Scholars Science Fund of the Natural Science Foundation of Hebei Province/ ; JZX2023002//Technology Project of Hebei Education Department/ ; 22JCQNJC01110//Tianjin Applied Basic Research Project/ ; 236Z2602G, 246Z2605G, 236Z2401G//the central government guides local funds for science and technology development for Hebei Province/ ; NV20230015//The Key Laboratory of Neural and Vascular Biology, Ministry of Education/ ; },
abstract = {Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water and ion metabolism by facilitating ion transport and participate in the physiological processes of neurons and glial cells by regulating signaling pathways. Neurodegenerative diseases are a group of disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Despite significant progress in understanding the pathophysiological processes of various neurological diseases in recent years, effective treatments for mitigating the damage caused by these diseases remain inadequate. Increasing evidence suggests that ion channels are closely associated with neuroinflammation; oxidative stress; and the characteristic proteins in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, studying the pathogenic mechanisms closely related to ion channels in neurodegenerative diseases can help identify more effective therapeutic targets for treating neurodegenerative diseases. Here, we discuss the progress of research on ion channels in different neurodegenerative diseases and emphasize the feasibility and potential of treating such diseases from the perspective of ion channels.},
}

@article {pmid39598254,
year = {2024},
author = {Ebert, ET and Schwinghamer, KM and Siahaan, TJ},
title = {Delivery of Neuroregenerative Proteins to the Brain for Treatments of Neurodegenerative Brain Diseases.},
journal = {Life (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/life14111456},
pmid = {39598254},
issn = {2075-1729},
abstract = {Neurodegenerative brain diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), and Parkinson's disease (PD) are difficult to treat. Unfortunately, many therapeutic agents for neurodegenerative disease only halt the progression of these diseases and do not reverse neuronal damage. There is a demand for finding solutions to reverse neuronal damage in the central nervous system (CNS) of patients with neurodegenerative brain diseases. Therefore, the purpose of this review is to discuss the potential for therapeutic agents like specific neurotrophic and growth factors in promoting CNS neuroregeneration in brain diseases. We discuss how BDNF, NGF, IGF-1, and LIF could potentially be used for the treatment of brain diseases. The molecule's different mechanisms of action in stimulating neuroregeneration and methods to analyze their efficacy are described. Methods that can be utilized to deliver these proteins to the brain are also discussed.},
}

@article {pmid39598187,
year = {2024},
author = {İzol, E and Turhan, M},
title = {In-Depth Phytochemical Profile by LC-MS/MS, Mineral Content by ICP-MS, and In-Vitro Antioxidant, Antidiabetic, Antiepilepsy, Anticholinergic, and Antiglaucoma Properties of Bitlis Propolis.},
journal = {Life (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/life14111389},
pmid = {39598187},
issn = {2075-1729},
abstract = {Propolis is very significant in terms of its phytochemical content and biological activity among bee products. In this study, the antioxidant activities (total phenolic and flavonoid, Fe[3+], Cu[2+] (CUPRAC), Fe[3+]-TPTZ (FRAP) reducing, and DPPH[•], ABTS[•+] scavenging assays) of propolis collected from the Bitlis province of Türkiye were determined. In addition, the carbonic anhydrase I and II isoenzymes (hCA I and hCA II), α-glycosidase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibition activity and phytochemical profile of propolis and mineral content were determined by LC-MS/MS and ICP-MS, respectively. In propolis, 31 phytochemicals were found, and the highest concentration of acacetin (23.604 mg/g) was detected. It is seen that the phytochemicals in propolis provide antioxidant properties. The mineral content was screened for 18 elements and determined to be rich in the elements that make up the salt content. Total phenolic content was 215.14 mg GAE/g, and total flavonoid content was 79.11 mg QE/g. The Fe[3+] reduction result was 0.940 (µg/mL), CUPRAC 1.183 (µg/mL), FRAP 0.963 (µg/mL), DPPH[•] scavenging IC50: 16.7 (µg/mL), and ABTS IC50: 8.01 (µg/mL). hCA I enzyme inhibition results in IC50: 7.19 (µg/mL), hCA II 8.15, AChE 5.17, BChE 7.50, and α-Glycosidase 5.72. As a result of this study, it was determined that Bitlis propolis has high antioxidant properties and a rich phytochemical content. It was also observed that it is an effective enzyme inhibitor against epilepsy, glaucoma, Alzheimer's, and diabetes, which are important diseases, and it can be evaluated in the treatment of these diseases and drug production.},
}

@article {pmid39598105,
year = {2024},
author = {Alhenaky, A and Alhazmi, S and Alamri, SH and Alkhatabi, HA and Alharthi, A and Alsaleem, MA and Abdelnour, SA and Hassan, SM},
title = {Exosomal MicroRNAs in Alzheimer's Disease: Unveiling Their Role and Pioneering Tools for Diagnosis and Treatment.},
journal = {Journal of clinical medicine},
volume = {13},
number = {22},
pages = {},
doi = {10.3390/jcm13226960},
pmid = {39598105},
issn = {2077-0383},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder that presents a significant health concern, often leading to substantial cognitive decline among older adults. A prominent feature of AD is progressive dementia, which eventually disrupts daily functioning and the ability to live independently. A major challenge in addressing AD is its prolonged pre-symptomatic phase, which makes early detection difficult. Moreover, the disease's complexity and the inefficiency of current diagnostic methods impede the development of targeted therapies. Therefore, there is an urgent need to enhance diagnostic methodologies for detection and treating AD even before clinical symptoms appear. Exosomes are nanoscale biovesicles secreted by cells, including nerve cells, into biofluids. These exosomes play essential roles in the central nervous system (CNS) by facilitating neuronal communication and thus influencing major physiological and pathological processes. Exosomal cargo, particularly microRNAs (miRNAs), are critical mediators in this cellular communication, and their dysregulation affects various pathological pathways related to neurodegenerative diseases, including AD. This review discusses the significant roles of exosomal miRNAs in the pathological mechanisms related to AD, focusing on the promising use of exosomal miRNAs as diagnostic biomarkers and targeted therapeutic interventions for this devastating disease.},
}

@article {pmid39597194,
year = {2024},
author = {Nanda, SS and Yi, DK},
title = {Exploring the Connection Between Nanomaterials and Neurodegenerative Disorders.},
journal = {Micromachines},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/mi15111382},
pmid = {39597194},
issn = {2072-666X},
abstract = {Drug delivery, tissue engineering, and cell promotion in biomedical fields heavily rely on the use of nanomaterials (NMs). When they penetrate cells, NPs undergo degradation and initiate the generation of reactive oxygen species (ROS) by causing changes in the structures of organelles linked to mitochondria. Inside the cell, the excess production of ROS can initiate a chain reaction, along with the autophagy process that helps maintain ROS balance by discarding unnecessary materials. At present, there is no effective treatment for Alzheimer's disease (AD), a progressive neurodegenerative disease. The use of NMs for siRNA delivery could become a promising treatment for AD and other CNS disorders. Recent research demonstrates that the use of combined NPs can induce autophagy in cells. This article emphasizes the importance of the shape of siRNA-encapsulated NMs in determining their efficiency in delivering and suppressing gene activity in the central nervous system. Because of its strict selectivity against foreign substances, the blood-brain barrier (BBB) significantly hinders the delivery of therapeutic agents to the brain. Conventional chemotherapeutic drugs are significantly less effective against brain cancers due to this limitation. As a result, NMs have become a promising approach for targeted drug delivery, as they can be modified to carry specific ligands that direct them to their intended targets. This review thoroughly examines the latest breakthroughs in using NMs to deliver bioactive compounds across the BBB, focusing on their use in cancer treatments. The review starts by examining the structure and functions of the BBB and BBTB, and then emphasizes the benefits that NMs offer.},
}

@article {pmid39596990,
year = {2024},
author = {Elariny, HA and Kabel, AM and Selim, HMRM and Helal, AI and Abdelrahman, D and Borg, HM and Elkady, MA and Dawood, LM and El-Badawy, MF and Almalawi, HFA and Arafa, EA and Alsufyani, SE and Arab, HH},
title = {Repositioning Canagliflozin for Mitigation of Aluminium Chloride-Induced Alzheimer's Disease: Involvement of TXNIP/NLRP3 Inflammasome Axis, Mitochondrial Dysfunction, and SIRT1/HMGB1 Signalling.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {60},
number = {11},
pages = {},
doi = {10.3390/medicina60111805},
pmid = {39596990},
issn = {1648-9144},
support = {TU-DSPP-2024-116//Taif University/ ; },
mesh = {Animals ; *Aluminum Chloride ; *Alzheimer Disease/drug therapy ; *Sirtuin 1/metabolism ; Rats ; *Canagliflozin/pharmacology/therapeutic use ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; HMGB1 Protein/metabolism ; Signal Transduction/drug effects ; Disease Models, Animal ; Mitochondria/drug effects/metabolism ; Male ; Inflammasomes/drug effects/metabolism ; Oxidative Stress/drug effects ; Cell Cycle Proteins/metabolism ; },
abstract = {Background and Objectives: Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world. Due to failure of the traditional drugs to produce a complete cure for AD, the search for new safe and effective lines of therapy has attracted the attention of ongoing research. Canagliflozin is an anti-diabetic agent with proven efficacy in the treatment of neurological disorders in which mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy play a pathophysiological role. Elucidation of the potential effects of different doses of canagliflozin on AD induced by aluminium chloride in rats and exploration of the molecular mechanisms that may contribute to these effects were the primary objectives of the current study. Materials and Methods: In a rat model of AD, the effect of three different doses of canagliflozin on the behavioural, biochemical, and histopathological alterations induced by aluminium chloride was assessed. Results: Canagliflozin administered to aluminium chloride-treated animals induced dose-dependent normalisation in the behavioural tests, augmentation of the antioxidant defence mechanisms, inhibition of TXNIP/NLRP3 inflammasome signalling, modulation of the SIRT1/HMGB1 axis, interference with the pro-inflammatory and the pro-apoptotic mechanisms, and restoration of the mitochondrial functions and autophagy in the hippocampal tissues to approximately baseline values. In addition, canagliflozin exhibited an interesting dose-dependent ability to repress aluminium chloride-induced histopathological changes in the brain. Conclusions: The effects of canagliflozin on oxidative stress, mitochondrial functions, inflammatory pathways, and autophagy signals may open new gates towards the mitigation of the pathologic features of AD.},
}

Animals
*Aluminum Chloride
*Alzheimer Disease/drug therapy
*Sirtuin 1/metabolism
Rats
*Canagliflozin/pharmacology/therapeutic use
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
HMGB1 Protein/metabolism
Signal Transduction/drug effects
Disease Models, Animal
Mitochondria/drug effects/metabolism
Male
Inflammasomes/drug effects/metabolism
Oxidative Stress/drug effects
Cell Cycle Proteins/metabolism

@article {pmid39596443,
year = {2024},
author = {Belousova, E and Salikhova, D and Maksimov, Y and Nebogatikov, V and Sudina, A and Goldshtein, D and Ustyugov, A},
title = {Proposed Mechanisms of Cell Therapy for Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {25},
number = {22},
pages = {},
doi = {10.3390/ijms252212378},
pmid = {39596443},
issn = {1422-0067},
support = {23-15-00362//Russian Science Foundation/ ; },
mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; Animals ; *Mitochondria/metabolism ; Cell- and Tissue-Based Therapy/methods ; Stem Cell Transplantation/methods ; Exosomes/metabolism/transplantation ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder characterized by mitochondria dysfunction, accumulation of beta-amyloid plaques, and hyperphosphorylated tau tangles in the brain leading to memory loss and cognitive deficits. There is currently no cure for this condition, but the potential of stem cells for the therapy of neurodegenerative pathologies is actively being researched. This review discusses preclinical and clinical studies that have used mouse models and human patients to investigate the use of novel types of stem cell treatment approaches. The findings provide valuable insights into the applications of stem cell-based therapies and include the use of neural, glial, mesenchymal, embryonic, and induced pluripotent stem cells. We cover current studies on stem cell replacement therapy where cells can functionally integrate into neural networks, replace damaged neurons, and strengthen impaired synaptic circuits in the brain. We address the paracrine action of stem cells acting via secreted factors to induce neuroregeneration and modify inflammatory responses. We focus on the neuroprotective functions of exosomes as well as their neurogenic and synaptogenic effects. We look into the shuttling of mitochondria through tunneling nanotubes that enables the transfer of healthy mitochondria by restoring the normal functioning of damaged cells, improving their metabolism, and reducing the level of apoptosis.},
}

*Alzheimer Disease/therapy/metabolism
Humans
Animals
*Mitochondria/metabolism
Cell- and Tissue-Based Therapy/methods
Stem Cell Transplantation/methods
Exosomes/metabolism/transplantation

@article {pmid39596305,
year = {2024},
author = {Mitroshina, EV and Kalinina, EP and Kalyakulina, AI and Teplyakova, AV and Vedunova, MV},
title = {The Effect of the Optogenetic Stimulation of Astrocytes on Neural Network Activity in an In Vitro Model of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {25},
number = {22},
pages = {},
doi = {10.3390/ijms252212237},
pmid = {39596305},
issn = {1422-0067},
support = {075-15-2022-293//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {*Astrocytes/metabolism ; *Optogenetics/methods ; *Alzheimer Disease/therapy/genetics/metabolism ; Animals ; Mice ; *Hippocampus/metabolism/cytology ; Nerve Net ; Cells, Cultured ; Glial Fibrillary Acidic Protein/metabolism/genetics ; Disease Models, Animal ; Channelrhodopsins/genetics/metabolism ; },
abstract = {Optogenetics is a combination of optical and genetic technologies used to activate or, conversely, inhibit specific cells in living tissues. The possibilities of using optogenetics approaches for the treatment of epilepsy, Parkinson's and Alzheimer's disease (AD) are being actively researched. In recent years, it has become clear that one of the most important players in the development of AD is astrocytes. Astrocytes affect amyloid clearance, participate in the development of neuroinflammation, and regulate the functioning of neural networks. We used an adeno-associated virus carrying the glial fibrillary acidic protein (GFAP) promoter driving the optogenetic channelrhodopsin-2 (ChR2) gene to transduce astrocytes in primary mouse hippocampal cultures. We recorded the bioelectrical activity of neural networks from day 14 to day 21 of cultivation using multielectrode arrays. A single optogenetic stimulation of astrocytes at 14 day of cultivation (DIV14) did not cause significant changes in neural network bioelectrical activity. Chronic optogenetic stimulation from DIV14 to DIV21 exerts a stimulatory effect on the bioelectrical activity of primary hippocampal cultures (the proportion of spikes included in network bursts significantly increased since DIV19). Moreover, chronic optogenetic stimulation over seven days partially preserved the activity and functional architecture of neuronal network in amyloidosis modeling. These results suggest that the selective optogenetic activation of astrocytes may represent a promising novel therapeutic strategy for combating AD.},
}

*Astrocytes/metabolism
*Optogenetics/methods
*Alzheimer Disease/therapy/genetics/metabolism
Animals
Mice
*Hippocampus/metabolism/cytology
Nerve Net
Cells, Cultured
Glial Fibrillary Acidic Protein/metabolism/genetics
Disease Models, Animal
Channelrhodopsins/genetics/metabolism

@article {pmid39596219,
year = {2024},
author = {Nguyen, QNS and Yoo, KY and Pham, TTT and Selvaraj, B and Vu, HT and Le, TT and Lee, H and Tran, QL and Thuong, PT and Pae, AN and Jung, SH and Lee, JW},
title = {Neuroprotective Effects of Ethanol Extract Polyscias guilfoylei (EEPG) Against Glutamate Induced Neurotoxicity in HT22 Cells.},
journal = {International journal of molecular sciences},
volume = {25},
number = {22},
pages = {},
doi = {10.3390/ijms252212153},
pmid = {39596219},
issn = {1422-0067},
support = {No. NRF-2019K1A3A1A82113697//National Research Foundation of Korea/ ; No. NDT.90.KR/20//Ministry of Science and Technology of Vietnam/ ; },
mesh = {Animals ; *Neuroprotective Agents/pharmacology ; *Glutamic Acid/toxicity/metabolism ; *Reactive Oxygen Species/metabolism ; *Plant Extracts/pharmacology ; Mice ; Rats ; *Oxidative Stress/drug effects ; Cell Line ; Ethanol/toxicity ; Calcium/metabolism ; Neurons/drug effects/metabolism ; Apoptosis/drug effects ; Cell Survival/drug effects ; Male ; Araliaceae/chemistry ; Brain Ischemia/drug therapy/metabolism ; },
abstract = {Oxidative stress induced by glutamate is a significant contributor to neuronal cell damage and can lead to neurodegenerative diseases such as Alzheimer's, Huntington's, and ischemic brain injury. At the cellular level, oxidative stress increases Ca[2+] ion influx and reactive oxygen species (ROS), which activate the MAPK signaling pathway. Additionally, the generation of ROS causes mitochondrial dysfunction, triggering apoptosis by promoting the translocation of AIF to the nucleus from the mitochondria. The neuroprotective potential of Polyscias guilfoylei has not yet been reported. Therefore, in this study, the ethanol extract of Polyscias guilfoylei (EEPG) was examined for its protective effect against oxidative cell damage caused by glutamate in neuronal cells. EEPG treatment increased the viability of HT22 cells exposed to high concentrations of glutamate. Cellular Ca[2+] ion influx and ROS generation decreased with EEPG treatment in glutamate-treated HT22 cells. EEPG treatment inhibited MAPK activation and AIF nuclear translocation. In an in vivo study, EEPG attenuated brain cell death in an ischemic brain injury rat model. This study demonstrates the potential therapeutic effects of Polyscias guilfoylei in the treatment of ischemic brain injury.},
}

Animals
*Neuroprotective Agents/pharmacology
*Glutamic Acid/toxicity/metabolism
*Reactive Oxygen Species/metabolism
*Plant Extracts/pharmacology
Mice
Rats
*Oxidative Stress/drug effects
Cell Line
Ethanol/toxicity
Calcium/metabolism
Neurons/drug effects/metabolism
Apoptosis/drug effects
Cell Survival/drug effects
Male
Araliaceae/chemistry
Brain Ischemia/drug therapy/metabolism

@article {pmid39596118,
year = {2024},
author = {Armeli, F and Coccurello, R and Giacovazzo, G and Mengoni, B and Paoletti, I and Oddi, S and Maccarrone, M and Businaro, R},
title = {FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models.},
journal = {International journal of molecular sciences},
volume = {25},
number = {22},
pages = {},
doi = {10.3390/ijms252212044},
pmid = {39596118},
issn = {1422-0067},
support = {PRIN 2017- 2017BTHJ4R, Ateneo 2020 RM120172B745088B, Ateneo 2021 RM12117A8166CD9//Ministry of University and Research (MUR), Sapienza University of Rome/ ; },
mesh = {Animals ; *Autophagy/drug effects ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Carbamates/pharmacology ; *Disease Models, Animal ; *Benzamides/pharmacology ; *Amidohydrolases/metabolism/antagonists & inhibitors ; *Microglia/drug effects/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Mice, Transgenic ; Endocannabinoids/metabolism ; TOR Serine-Threonine Kinases/metabolism ; },
abstract = {Endocannabinoids have attracted great interest for their ability to counteract the neuroinflammation underlying Alzheimer's disease (AD). Our study aimed at evaluating whether this activity was also due to a rebalance of autophagic mechanisms in cellular and animal models of AD. We supplied URB597, an inhibitor of Fatty-Acid Amide Hydrolase (FAAH), the degradation enzyme of anandamide, to microglial cultures treated with Aβ25-35, and to Tg2576 transgenic mice, thus increasing the endocannabinoid tone. The addition of URB597 did not alter cell viability and induced microglia polarization toward an anti-inflammatory phenotype, as shown by the modulation of pro- and anti-inflammatory cytokines, as well as M1 and M2 markers; moreover microglia, after URB597 treatment released higher levels of Bdnf and Nrf2, confirming the protective role underlying endocannabinoids increase, as shown by RT-PCR and immunofluorescence experiments. We assessed the number and area of amyloid plaques in animals administered with URB597 compared to untreated animals and the expression of autophagy key markers in the hippocampus and prefrontal cortex from both groups of mice, via immunohistochemistry and ELISA. After URB597 supply, we detected a reduction in the number and areas of amyloid plaques, as detected by Congo Red staining and a reshaping of microglia activation as shown by M1 and M2 markers' modulation. URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD.},
}

Animals
*Autophagy/drug effects
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
*Carbamates/pharmacology
*Disease Models, Animal
*Benzamides/pharmacology
*Amidohydrolases/metabolism/antagonists & inhibitors
*Microglia/drug effects/metabolism
*Neuroinflammatory Diseases/drug therapy/metabolism
*Mice, Transgenic
Endocannabinoids/metabolism
TOR Serine-Threonine Kinases/metabolism

@article {pmid39596023,
year = {2024},
author = {Kciuk, M and Kruczkowska, W and Gałęziewska, J and Wanke, K and Kałuzińska-Kołat, Ż and Aleksandrowicz, M and Kontek, R},
title = {Alzheimer's Disease as Type 3 Diabetes: Understanding the Link and Implications.},
journal = {International journal of molecular sciences},
volume = {25},
number = {22},
pages = {},
doi = {10.3390/ijms252211955},
pmid = {39596023},
issn = {1422-0067},
mesh = {*Alzheimer Disease/metabolism/etiology/pathology ; Humans ; *Diabetes Mellitus, Type 2/metabolism ; *Insulin Resistance ; Oxidative Stress ; Animals ; Insulin/metabolism ; },
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent conditions that present considerable public health issue in aging populations worldwide. Recent research has proposed a novel conceptualization of AD as "type 3 diabetes", highlighting the critical roles of insulin resistance and impaired glucose metabolism in the pathogenesis of the disease. This article examines the implications of this association, exploring potential new avenues for treatment and preventive strategies for AD. Key evidence linking diabetes to AD emphasizes critical metabolic processes that contribute to neurodegeneration, including inflammation, oxidative stress, and alterations in insulin signaling pathways. By framing AD within this metabolic context, we can enhance our understanding of its etiology, which in turn may influence early diagnosis, treatment plans, and preventive measures. Understanding AD as a manifestation of diabetes opens up the possibility of employing novel therapeutic strategies that incorporate lifestyle modifications and the use of antidiabetic medications to mitigate cognitive decline. This integrated approach has the potential to improve patient outcomes and deepen our comprehension of the intricate relationship between neurodegenerative diseases and metabolic disorders.},
}

*Alzheimer Disease/metabolism/etiology/pathology
Humans
*Diabetes Mellitus, Type 2/metabolism
*Insulin Resistance
Oxidative Stress
Animals
Insulin/metabolism

@article {pmid39595863,
year = {2024},
author = {Fonte, C and Rotundo, G and Varalta, V and Filosa, A and Muti, E and Barletta, C and Evangelista, E and Venturelli, M and Picelli, A and Smania, N},
title = {Combined Effect of tDCS and Motor or Cognitive Activity in Patients with Alzheimer's Disease: A Proof-of-Concept Pilot Study.},
journal = {Brain sciences},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/brainsci14111099},
pmid = {39595863},
issn = {2076-3425},
abstract = {(1) Background: Alzheimer's disease (AD) accounts for 70% of dementia cases and with no effective pharmacological treatments, new rehabilitation methods are needed. Motor and cognitive activities and transcranial direct current stimulation (tDCS) have shown promise in stabilizing and enhancing cognitive functions. Objective: we want to investigate the effects of tDCS combined with motor or cognitive activity on cognitive functions in AD patients. (2) Methods: Patients with mild or moderate AD were randomized between anodic tDCS groups (MotA or CogA) and sham tDCS groups (MotS or CogS). They received two weeks of treatment (45 min, five days/week), with the first 15 min using tDCS stimulation on the dorsolateral prefrontal cortex. Cognitive assessments were conducted pre-treatment (T0), post-treatment (T1), and one week after (T2). (3) Results: Twenty-three patients were included. Statistical analysis showed significant differences between anodic tDCS groups (MotA + CogA) and sham tDCS groups (MotS + CogS) with advantages for the first in improving global cognitive status (p = 0.042), selective attention (p = 0.012), and sustained attention (p = 0.012). Further analysis indicated no differences between the two anodic tDCS groups between T0 and T1. (4) Conclusions: combined anodal tDCS with motor or cognitive activity could improve global cognitive state and attention, slowing cognitive decline in AD patients. The trial was registered on Clinical Trials: NCT06619795.},
}

@article {pmid39595846,
year = {2024},
author = {Costa, ACS},
title = {On the Therapeutic Use of Monoclonal Antibodies Against Amyloid Plaques in Older Adults with Down Syndrome: A Narrative Review and Perspective.},
journal = {Brain sciences},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/brainsci14111084},
pmid = {39595846},
issn = {2076-3425},
support = {N/A//Center for Neurodegenerative Disorders (CENDIVE) at University Hospitals Cleveland/ ; N/A//Awakening Angels Foundation/ ; R03AG086928/GF/NIH HHS/United States ; 3U24AG057437/GF/NIH HHS/United States ; },
abstract = {Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21 (trisomy 21 or T21) and is associated with an increased risk of early-onset Alzheimer's disease (AD), also known as DS-associated AD (DSAD). Individuals with DS typically develop amyloid neuropathology in their late-thirties to early-forties and the mean age of onset of clinical dementia is approximately 55 years. Recent advances in AD clinical research have focused on monoclonal antibodies (mAbs) targeting amyloid-β (Aβ) plaques as a potential therapeutic approach. Therefore, there has been guarded enthusiasm about using anti-amyloid mAbs in the prevention/treatment of DSAD. This narrative review and perspective explores the current understanding of amyloid pathology in AD and DSAD, the rationale for using anti-amyloid mAbs in the treatment of DSAD, and the challenges and opportunities for research toward the application of this therapeutic strategy to older adults with DS.},
}

@article {pmid39595827,
year = {2024},
author = {Wang, M and Dinarvand, D and Chan, CTY and Bragin, A and Li, L},
title = {Photobiomodulation as a Potential Treatment for Alzheimer's Disease: A Review Paper.},
journal = {Brain sciences},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/brainsci14111064},
pmid = {39595827},
issn = {2076-3425},
support = {1RF1NS033310-27S1/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, is a leading neurodegenerative disorder currently affecting approximately 55 million individuals globally, a number projected to escalate to 139 million by 2050. Despite extensive research spanning several decades, the cure for AD remains at a developing stage. The only existing therapeutic options are limited to symptom management, and are often accompanied by adverse side effects. The pathological features of AD, including the accumulation of beta-amyloid plaques and tau protein tangles, result in progressive neuronal death, synaptic loss, and brain atrophy, leading to significant cognitive decline and a marked reduction in quality of life.

OBJECTIVE: In light of the shortcomings of existing pharmacological interventions, this review explores the potential of photobiomodulation (PBM) as a non-invasive therapeutic option for AD. PBM employs infrared light to facilitate cellular repair and regeneration, focusing on addressing the disease's underlying biomechanical mechanisms.

METHOD: This paper presents a comprehensive introduction to the mechanisms of PBM and an analysis of preclinical studies evaluating its impact on cellular health, cognitive function, and disease progression in AD.The review provides a comprehensive overview of the various wavelengths and application methods, evaluating their efficacy in mitigating AD-related symptoms.

CONCLUSIONS: The findings underscore the significant potential of PBM as a safe and effective alternative treatment for Alzheimer's disease, emphasizing the necessity for further research and clinical trials to establish its therapeutic efficacy conclusively.},
}

@article {pmid39595812,
year = {2024},
author = {Zhang, S and Yang, Y and Lv, X and Zhou, X and Zhao, W and Meng, L and Zhu, S and Zhang, Z and Wang, Y},
title = {Exosome Cargo in Neurodegenerative Diseases: Leveraging Their Intercellular Communication Capabilities for Biomarker Discovery and Therapeutic Delivery.},
journal = {Brain sciences},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/brainsci14111049},
pmid = {39595812},
issn = {2076-3425},
support = {82171871//National Natural Science Foundation of China/ ; BK20230488//Youth Fund Project of the Jiangsu Province Basic Research Program (Natural Science Foundation)/ ; None//Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; },
abstract = {The inexorable progression of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, is closely related to irreversible brain decline. Accurately characterizing pathophysiological features and identifying reliable biomarkers for early diagnosis and optimized treatment are critical. Hindered by the blood-brain barrier (BBB), obtaining sensitive monitoring indicators for disease progression and achieving efficient drug delivery remain significant challenges. Exosomes, endogenous nanoscale vesicles that carry key bioactive substances, reflect the intracellular environment and play an important role in cell signaling. They have shown promise in traversing the BBB, serving dual roles as potential biomarkers for NDs and vehicles for targeted drug delivery. However, the specific mechanisms by which exosome influence NDs are not fully understood, necessitating further investigation into their attributes and functionalities in the context of NDs. This review explores how exosomes mediate multifaceted interactions, particularly in exacerbating pathogenic processes such as oxidative stress, neuronal dysfunction, and apoptosis integral to NDs. It provides a comprehensive analysis of the profound impact of exosomes under stress and disease states, assessing their prospective utility as biomarkers and drug delivery vectors, offering new perspectives for tackling these challenging diseases.},
}

@article {pmid39595200,
year = {2024},
author = {Qi, X and Nizamutdinov, D and Yi, SS and Wu, E and Huang, JH},
title = {Disease Modifying Monoclonal Antibodies and Symptomatic Pharmacological Treatment for Alzheimer's Disease.},
journal = {Biomedicines},
volume = {12},
number = {11},
pages = {},
pmid = {39595200},
issn = {2227-9059},
abstract = {Alzheimer's Disease (AD) is an irreversible, progressive syndrome characterized by neurocognitive impairment. Two neuropathological features seen in AD are extracellular amyloid plaques consisting of amyloid beta1-40 and 1-42, and intracellular neurofibrillary tangles (NFTs). For decades, neuroscience research has heavily focused on seeking to understand the primary mechanism of AD and searching for pharmacological approaches for the treatment of dementia. Three monoclonal antibodies that act against amyloid beta-aducanumab, lecanemab, and donanemab-have been approved by the Food and Drug Administration (FDA) for the treatment of mild cognitive impairment and mild AD, in addition to medications for cognitive symptom management such as acetylcholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) antagonist. Further trials should focus on the combination of therapies targeting amyloid plaques and tau pathology.},
}

@article {pmid39595072,
year = {2024},
author = {Sharbafshaaer, M and Cirillo, G and Esposito, F and Tedeschi, G and Trojsi, F},
title = {Harnessing Brain Plasticity: The Therapeutic Power of Repetitive Transcranial Magnetic Stimulation (rTMS) and Theta Burst Stimulation (TBS) in Neurotransmitter Modulation, Receptor Dynamics, and Neuroimaging for Neurological Innovations.},
journal = {Biomedicines},
volume = {12},
number = {11},
pages = {},
pmid = {39595072},
issn = {2227-9059},
abstract = {Transcranial magnetic stimulation (TMS) methods have become exciting techniques for altering brain activity and improving synaptic plasticity, earning recognition as valuable non-medicine treatments for a wide range of neurological disorders. Among these methods, repetitive TMS (rTMS) and theta-burst stimulation (TBS) show significant promise in improving outcomes for adults with complex neurological and neurodegenerative conditions, such as Alzheimer's disease, stroke, Parkinson's disease, etc. However, optimizing their effects remains a challenge due to variability in how patients respond and a limited understanding of how these techniques interact with crucial neurotransmitter systems. This narrative review explores the mechanisms of rTMS and TBS, which enhance neuroplasticity and functional improvement. We specifically focus on their effects on GABAergic and glutamatergic pathways and how they interact with key receptors like N-Methyl-D-Aspartate (NMDA) and AMPA receptors, which play essential roles in processes like long-term potentiation (LTP) and long-term depression (LTD). Additionally, we investigate how rTMS and TBS impact neuroplasticity and functional connectivity, particularly concerning brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase receptor type B (TrkB). Here, we highlight the significant potential of this research to expand our understanding of neuroplasticity and better treatment outcomes for patients. Through clarifying the neurobiology mechanisms behind rTMS and TBS with neuroimaging findings, we aim to develop more effective, personalized treatment plans that effectively address the challenges posed by neurological disorders and ultimately enhance the quality of neurorehabilitation services and provide future directions for patients' care.},
}

@article {pmid39595009,
year = {2024},
author = {Moyano, P and Guzmán, G and Flores, A and García, J and Guerra-Menéndez, L and Sanjuan, J and Plaza, JC and Abascal, L and Mateo, O and Del Pino, J},
title = {Thyroid Hormone Neuroprotection Against Perfluorooctane Sulfonic Acid Cholinergic and Glutamatergic Disruption and Neurodegeneration Induction.},
journal = {Biomedicines},
volume = {12},
number = {11},
pages = {},
pmid = {39595009},
issn = {2227-9059},
support = {PR26/20326//Santander Bank/UCM/ ; 72C126PMA//Alborada Foundation/Cátedra Extraordinaria de Patología y Medioambiente, UCM./ ; },
abstract = {Background: Perfluorooctane sulfonic acid (PFOS), a widely used industrial chemical, was reported to induce memory and learning process dysfunction. Some studies tried to reveal the mechanisms that mediate these effects, but how they are produced is still unknown. Basal forebrain cholinergic neurons (BFCN) maintain cognitive function and their selective neurodegeneration induces cognitive decline, as observed in Alzheimer's disease. PFOS was reported to disrupt cholinergic and glutamatergic transmissions and thyroid hormone action, which regulate cognitive processes and maintain BFCN viability. Objective/Methods: To evaluate PFOS neurodegenerative effects on BFCN and the mechanisms that mediate them, SN56 cells (a neuroblastoma cholinergic cell line from the basal forebrain) were treated with PFOS (0.1 µM to 40 µM) with or without thyroxine (T3; 15 nM), MK-801 (20 µM) or acetylcholine (ACh; 10 µM). Results: In the present study, we found that PFOS treatment (1 or 14 days) decreased thyroid receptor α (TRα) activity by decreasing its protein levels and increased T3 metabolism through increased deiodinase 3 (D3) levels. Further, we observed that PFOS treatment disrupted cholinergic transmission by decreasing ACh content through decreased choline acetyltransferase (ChAT) activity and protein levels and through decreasing muscarinic receptor 1 (M1R) binding and protein levels. PFOS also disrupted glutamatergic transmission by decreasing glutamate content through increased glutaminase activity and protein levels and through decreasing N-methyl-D-aspartate receptor subunit 1 (NMDAR1); effects mediated through M1R disruption. All these effects were mediated through decreased T3 activity and T3 supplementation partially restored to the normal state. Conclusions: These findings may assist in understanding how PFOS induces neurodegeneration, and the mechanisms involved, especially in BFCN, to explain the process that could lead to cognitive dysfunction and provide new therapeutic tools to treat and prevent its neurotoxic effects.},
}

@article {pmid39594648,
year = {2024},
author = {El Abiad, E and Al-Kuwari, A and Al-Aani, U and Al Jaidah, Y and Chaari, A},
title = {Navigating the Alzheimer's Biomarker Landscape: A Comprehensive Analysis of Fluid-Based Diagnostics.},
journal = {Cells},
volume = {13},
number = {22},
pages = {},
doi = {10.3390/cells13221901},
pmid = {39594648},
issn = {2073-4409},
support = {SRMP-7-6452//Weill Cornell Medicine - Qatar/ ; },
mesh = {*Alzheimer Disease/diagnosis/cerebrospinal fluid/metabolism ; Humans ; *Biomarkers/cerebrospinal fluid/metabolism/blood ; Saliva/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) affects a significant portion of the aging population, presenting a serious challenge due to the limited availability of effective therapies during its progression. The disease advances rapidly, underscoring the need for early diagnosis and the application of preventative measures. Current diagnostic methods for AD are often expensive and invasive, restricting access for the general public. One potential solution is the use of biomarkers, which can facilitate early detection and treatment through objective, non-invasive, and cost-effective evaluations of AD. This review critically investigates the function and role of biofluid biomarkers in detecting AD, with a specific focus on cerebrospinal fluid (CSF), blood-based, and saliva biomarkers.

RESULTS: CSF biomarkers have demonstrated potential for accurate diagnosis and valuable prognostic insights, while blood biomarkers offer a minimally invasive and cost-effective approach for diagnosing cognitive issues. However, while current biomarkers for AD show significant potential, none have yet achieved the precision needed to replace expensive PET scans and CSF assays. The lack of a single accurate biomarker underscores the need for further research to identify novel or combined biomarkers to enhance the clinical efficacy of existing diagnostic tests. In this context, artificial intelligence (AI) and deep-learning (DL) tools present promising avenues for improving biomarker analysis and interpretation, enabling more precise and timely diagnoses.

CONCLUSIONS: Further research is essential to confirm the utility of all AD biomarkers in clinical settings. Combining biomarker data with AI tools offers a promising path toward revolutionizing the personalized characterization and early diagnosis of AD symptoms.},
}

*Alzheimer Disease/diagnosis/cerebrospinal fluid/metabolism
Humans
*Biomarkers/cerebrospinal fluid/metabolism/blood
Saliva/metabolism

@article {pmid39594552,
year = {2024},
author = {Budamagunta, MS and Mori, H and Silk, J and Slez, RR and Bognár, B and Mendiola, UR and Kálai, T and Maezawa, I and Voss, JC},
title = {Nitroxyl Hybrids with Curcumin and Stilbene Scaffolds Display Potent Antioxidant Activity, Remodel the Amyloid Beta Oligomer, and Reverse Amyloid Beta-Induced Cytotoxicity.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/antiox13111411},
pmid = {39594552},
issn = {2076-3921},
support = {NKFI K 137793//National Research, Development, and Innovation Fund of Hungary/ ; P30 AG010129/NH/NIH HHS/United States ; RF1 AG071665/NH/NIH HHS/United States ; },
abstract = {The disorder and heterogeneity of low-molecular-weight amyloid-beta oligomers (AβOs) underlie their participation in multiple modes of cellular dysfunction associated with the etiology of Alzheimer's disease (AD). The lack of specified conformational states in these species complicates efforts to select or design small molecules to targeting discrete pathogenic states. Furthermore, targeting AβOs alone may be therapeutically insufficient, as AD progresses as a multifactorial, self-amplifying cascade. To address these challenges, we have screened the activity of seven new candidates that serve as Paramagnetic Amyloid Ligand (PAL) candidates. PALs are bifunctional small molecules that both remodel the AβO structure and localize a potent antioxidant that mimics the activity of SOD within live cells. The candidates are built from either a stilbene or curcumin scaffold with nitroxyl moiety to serve as catalytic antioxidants. Measurements of PAL AβO binding and remolding along with assessments of bioactivity allow for the extraction of useful SAR information from screening data. One candidate (HO-4450; PMT-307), with a six-membered nitroxyl ring attached to a stilbene ring, displays the highest potency in protecting against cell-derived Aβ. A preliminary low-dose evaluation in AD model mice provides evidence of modest treatment effects by HO-4450. The results for the curcumin PALs demonstrate that the retention of the native curcumin phenolic groups is advantageous to the design of the hybrid PAL candidates. Finally, the PAL remodeling of AβO secondary structures shows a reasonable correlation between a candidate's bioactivity and its ability to reduce the fraction of antiparallel β-strand.},
}

@article {pmid39593736,
year = {2024},
author = {Ali, MU and Hussain, SJ and Khalid, M and Farrash, M and Lahza, HFM and Zafar, A},
title = {MRI-Driven Alzheimer's Disease Diagnosis Using Deep Network Fusion and Optimal Selection of Feature.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {11},
number = {11},
pages = {},
pmid = {39593736},
issn = {2306-5354},
abstract = {Alzheimer's disease (AD) is a degenerative neurological condition characterized by cognitive decline, memory loss, and reduced everyday function, which eventually causes dementia. Symptoms develop years after the disease begins, making early detection difficult. While AD remains incurable, timely detection and prompt treatment can substantially slow its progression. This study presented a framework for automated AD detection using brain MRIs. Firstly, the deep network information (i.e., features) were extracted using various deep-learning networks. The information extracted from the best deep networks (EfficientNet-b0 and MobileNet-v2) were merged using the canonical correlation approach (CCA). The CCA-based fused features resulted in an enhanced classification performance of 94.7% with a large feature vector size (i.e., 2532). To remove the redundant features from the CCA-based fused feature vector, the binary-enhanced WOA was utilized for optimal feature selection, which yielded an average accuracy of 98.12 ± 0.52 (mean ± standard deviation) with only 953 features. The results were compared with other optimal feature selection techniques, showing that the binary-enhanced WOA results are statistically significant (p < 0.01). The ablation study was also performed to show the significance of each step of the proposed methodology. Furthermore, the comparison shows the superiority and high classification performance of the proposed automated AD detection approach, suggesting that the hybrid approach may help doctors with dementia detection and staging.},
}

@article {pmid39592934,
year = {2024},
author = {Mottolese, N and Loi, M and Trazzi, S and Tassinari, M and Uguagliati, B and Candini, G and Iqbal, K and Medici, G and Ciani, E},
title = {Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.},
journal = {Journal of neurodevelopmental disorders},
volume = {16},
number = {1},
pages = {65},
pmid = {39592934},
issn = {1866-1955},
mesh = {Animals ; *Spasms, Infantile/drug therapy/genetics ; *Epileptic Syndromes/drug therapy ; Mice ; *Disease Models, Animal ; *Protein Serine-Threonine Kinases/genetics/metabolism ; *Mice, Knockout ; *Ciliary Neurotrophic Factor/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Humans ; Neurons/drug effects/metabolism ; Neurogenesis/drug effects ; Male ; },
abstract = {BACKGROUND: Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer's disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expression, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD.

METHODS: We used SH-CDKL5-KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects.

RESULTS: We found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 KO mice, resulting in limited behavioral benefit.

CONCLUSIONS: At present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro.},
}

Animals
*Spasms, Infantile/drug therapy/genetics
*Epileptic Syndromes/drug therapy
Mice
*Disease Models, Animal
*Protein Serine-Threonine Kinases/genetics/metabolism
*Mice, Knockout
*Ciliary Neurotrophic Factor/pharmacology
Brain-Derived Neurotrophic Factor/metabolism/drug effects
Humans
Neurons/drug effects/metabolism
Neurogenesis/drug effects
Male

@article {pmid39592536,
year = {2024},
author = {Nemr, MTM and Abdelaziz, MA and Teleb, M and Elmasry, AE and Elshaier, YAAM},
title = {An overview on pharmaceutical applications of phosphodiesterase enzyme 5 (PDE5) inhibitors.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {39592536},
issn = {1573-501X},
abstract = {Phosphodiesterase enzyme 5 (PDE5) inhibitors have emerged as one of the leading molecules for the treatment of erectile dysfunction (ED). PDE5 inhibitors are categorized structurally into several classes. PDE5 inhibitors have been a multidisciplinary endeavor that attracts the attention of researchers because of their multiple pharmaceutical applications. Beyond their action on ED, PDE5 inhibitors are widely used in treatment of benign prostatic hypertrophy (BPH), Eisenmenger's syndrome, Raynaud's Disease, Intrauterine growth retardation (IUGR), Mountain sickness, Bladder pain syndrome/interstitial cystitis (BPS/IC), pulmonary arterial hypertension and type II diabetes (insulin resistance). In addition, PDE5 inhibitors also show promising antiproliferative activity, anti-Alzheimer and COX-1/COX-2 inhibitory activity (anti-inflammatory). Pharmacokinetics, Pharmacogenetics and toxicity of PDE5 inhibitors were finally explored. The diverse therapeutic applications, the high feasibility of structural modification and the appropriate pharmacokinetic properties of PDE5 inhibitors have motivated researchers to develop new scaffolds that have been either under clinical trials or approved by FDA and utilize them to overcome some recent global concerns, such as COVID-19.},
}

@article {pmid39591987,
year = {2024},
author = {Permana, AD and Mahfud, MAS and Munir, M and Aries, A and Rezka Putra, A and Fikri, A and Setiawan, H and Mahendra, I and Rizaludin, A and Ramadhani Aziz, AY and Djabir, YY and Arsyad, A and Harahap, Y and Saputri, WD and Fajarwati, R and Darmawan, N},
title = {A Combinatorial Approach with Microneedle Pretreatment and Thermosensitive Gel Loaded with Rivastigmine Lipid Nanoparticle Formulation Enables Brain Delivery via the Trigeminal Nerve.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.4c16024},
pmid = {39591987},
issn = {1944-8252},
abstract = {Alzheimer's disease (AD) often leads to dementia, causing cognitive decline and increased care needs. Rivastigmine (RV) is a key AD treatment, but its brain delivery is limited by the blood-brain barrier (BBB). Aside from oral, olfactory, and intradermal injection (i.d.) routes, the application of polymeric microneedles via the trigeminal nerve on the facial skin as a pretreatment, followed by a solid lipid nanoparticle RV-loaded thermosensitive gel (PMN-SLN-RV-TG), is an alternative to deal with the problems. This study aims to determine the optimal formula for PMN-SLN-RV-TG application and assess its brain delivery ability compared to conventional routes. The optimum SLN-RV formula had a particle size <200 nm and sustained release for 72 h, which was selected for the SLN-RV-TG formulation. SLN-RV-TG was transformed into a gel at normal skin temperature (32-37 °C), with good physical properties and nontoxic behavior. The ideal PMN formula was able to penetrate the dermal layer as an alternative to i.d. administration. Ex vivo dermatokinetics showed significant improvement of PMN-SLN-RV-TG application (p < 0.05) compared to without PMN application. In vivo pharmacokinetic studies on rats also revealed that the PMN-SLN-RV-TG had superior pharmacokinetic parameters (Cmax, AUC, t1/2, and MRT) compared to other groups (p < 0.05). Radiolabeling SLN-RV with [99m]Tc showed good physical properties, with a radiochemical yield of >95%. In vivo distribution studies of PMN-SLN-RV-TG application exhibited a higher brain:blood ratio than i.v. administration after 5 h, as well as being safe for the brain due to a good histological profile. These results show that PMN-SLN-RV-TG application via the trigeminal nerve on the facial skin has strong potential delivery to the brain for AD treatment.},
}

@article {pmid39591666,
year = {2024},
author = {Prickaerts, J and Kerckhoffs, J and Possemis, N and van Overveld, W and Verbeek, F and Grooters, T and Sambeth, A and Blokland, A},
title = {Roflumilast and cognition enhancement: A translational perspective.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {181},
number = {},
pages = {117707},
doi = {10.1016/j.biopha.2024.117707},
pmid = {39591666},
issn = {1950-6007},
abstract = {Cognitive impairment affiliated with neurological disorders has a severe impact on daily life functioning and the quality of life of patients. This is associated with a significant and long-lasting health, social and financial burden, not only for the patients, but also for families and the wider society. However, treatment for cognitive impairment is only available for the indication Alzheimer's disease (AD) and its prodromal stage Mild Cognitive Impairment (MCI), although with major adverse effects, i.e. gastrointestinal effects (drugs) or hemorrhages (antibodies). Roflumilast (selective phosphodiesterase type 4 (PDE4) inhibitor) has been approved as an anti-inflammatory drug for the treatment of chronic obstructive pulmonary disease (COPD), although still 5 % of the patients experience nausea or even vomiting at the approved dose of 500 μg. Nonclinical studies demonstrated that roflumilast appears a promising drug the treat cognitive impairment in healthy rodents and a wide variety of animal models of CNS disorders. These effects are attributed to pro-neuroplasticity and anti-inflammatory effects, which appeared dose dependent. Roflumilast has also been tested in clinical studies and showed cognition enhancement at low dosing (100-250 µg) in healthy adults, healthy elderly, MCI and schizophrenia. Currently, clinical trials are underway for testing the pro-cognitive effects in early AD, post stroke cognitive impairment and Fragile X. Overall, the data showed that roflumilast has beneficial effects on cognitive performance. These cognition-enhancing effects are found at doses that were well-tolerated. Based on this favorable therapeutic window, the repurposing of roflumilast for treating cognitive impairments in CNS diseases may offer an affordable treatment option for patients.},
}